Review Article Mutations in the ATP13A2 Gene and Parkinsonism: A Preliminary...
10
Review Article Mutations in the ATP13A2 Gene and Parkinsonism: A Preliminary Review Xinglong Yang and Yanming Xu Department of Neurology, West China Hospital, Sichuan University, 37 Guo Xue Xiang, Chengdu, Sichuan 610041, China Correspondence should be addressed to Yanming Xu; [email protected] Received 22 May 2014; Revised 14 July 2014; Accepted 28 July 2014; Published 14 August 2014 Academic Editor: Hiroyuki Tomiyama Copyright © 2014 X. Yang and Y. Xu. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Parkinson’s disease (PD) is a major neurodegenerative disorder for which the etiology and pathogenesis remain as elusive as for Alzheimer’s disease. PD appears to be caused by genetic and environmental factors, and pedigree and cohort studies have identified numerous susceptibility genes and loci related to PD. Autosomal recessive mutations in the genes Parkin, Pink1, DJ- 1, ATP13A2, PLA2G6, and FBXO7 have been linked to PD susceptibility. Such mutations in ATP13A2, also named PARK9, were first identified in 2006 in a Chilean family and are associated with a juvenile-onset, levodopa-responsive type of Parkinsonism called Kufor-Rakeb syndrome (KRS). KRS involves pyramidal degeneration, supranuclear palsy, and cognitive impairment. Here we review current knowledge about the ATP13A2 gene, clinical characteristics of patients with PD-associated ATP13A2 mutations, and models of how the ATP13A2 protein may help prevent neurodegeneration by inhibiting -synuclein aggregation and supporting normal lysosomal and mitochondrial function. We also discuss another ATP13A2 mutation that is associated with the family of neurodegenerative disorders called neuronal ceroid lipofuscinoses (NCLs), and we propose a single pathway whereby ATP13A2 mutations may contribute to NCLs and Parkinsonism. Finally, we highlight how studies of mutations in this gene may provide new insights into PD pathogenesis and identify potential therapeutic targets. 1. Introduction Parkinson’s disease (PD) is a neurodegenerative disorder for which the etiology and pathogenesis remain elusive, although it is known to be a multifactorial disease involving both genetic and environmental factors. Pedigree and cohort studies of patients with inherited forms of PD, which account for only 5–10% of cases [1], have identified numerous genes and loci associated with PD susceptibility [2, 3]. Autosomal recessive mutations in six of these genes have been linked to the disease: Parkin (PARK2)[4], DJ-1 (PARK7 )[5], PINK1 (PARK6)[6], ATP13A2 (PARK9)[7], PLA2G6 (PARK14)[8], and FBXO7 (PARK15)[9]. Autosomal recessive mutations in the ATP13A2 gene were first discovered in 2006 in a single Chilean pedigree [7]. Several members of the family showed a rare, juvenile-onset, levodopa-responsive type of Parkinsonism named Kufor- Rakeb syndrome (KRS), involving pyramidal degeneration, supranuclear palsy, and cognitive impairment. Subsequent studies in several other countries linked other mutations to KRS and early-onset Parkinsonism. At the same time, ATP13A2 mutations have been associated with the occurrence of neurodegenerative disorders called neuronal ceroid lipo- fuscinoses (NCLs) in patients with Parkinsonism [10]. Some of the NCL-associated mutations overlap with PD-associated ones, suggesting a common pathway in the two types of neurological disease. Here, we review recent advances in the emerging associ- ation of ATP13A2 mutations with Parkinsonism and NCLs. ese findings point to the gene and/or protein as a potential therapeutic target. 2. ATP13A2 Mutations and PD In the first study linking ATP13A2 mutations to PD, pedigree analysis of one Chilean family with several members with KRS led to the identification of two loss-of-function muta- tions: c.1306+5G>A in exon 13 and 3057delC/1019GfsX1021 Hindawi Publishing Corporation BioMed Research International Volume 2014, Article ID 371256, 9 pages http://dx.doi.org/10.1155/2014/371256
Transcript of Review Article Mutations in the ATP13A2 Gene and Parkinsonism: A Preliminary...
Review ArticleMutations in the ATP13A2 Gene and ParkinsonismA Preliminary Review
Xinglong Yang and Yanming Xu
Department of Neurology West China Hospital Sichuan University 37 Guo Xue Xiang Chengdu Sichuan 610041 China
Correspondence should be addressed to Yanming Xu neuroxym999163com
Received 22 May 2014 Revised 14 July 2014 Accepted 28 July 2014 Published 14 August 2014
Academic Editor Hiroyuki Tomiyama
Copyright copy 2014 X Yang and Y Xu This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited
Parkinsonrsquos disease (PD) is a major neurodegenerative disorder for which the etiology and pathogenesis remain as elusive asfor Alzheimerrsquos disease PD appears to be caused by genetic and environmental factors and pedigree and cohort studies haveidentified numerous susceptibility genes and loci related to PD Autosomal recessive mutations in the genes Parkin Pink1 DJ-1 ATP13A2 PLA2G6 and FBXO7 have been linked to PD susceptibility Such mutations in ATP13A2 also named PARK9 werefirst identified in 2006 in a Chilean family and are associated with a juvenile-onset levodopa-responsive type of ParkinsonismcalledKufor-Rakeb syndrome (KRS) KRS involves pyramidal degeneration supranuclear palsy and cognitive impairment Herewereview current knowledge about theATP13A2 gene clinical characteristics of patients with PD-associatedATP13A2mutations andmodels of how the ATP13A2 protein may help prevent neurodegeneration by inhibiting 120572-synuclein aggregation and supportingnormal lysosomal and mitochondrial function We also discuss another ATP13A2 mutation that is associated with the family ofneurodegenerative disorders called neuronal ceroid lipofuscinoses (NCLs) and we propose a single pathway whereby ATP13A2mutations may contribute to NCLs and Parkinsonism Finally we highlight how studies of mutations in this gene may provide newinsights into PD pathogenesis and identify potential therapeutic targets
1 Introduction
Parkinsonrsquos disease (PD) is a neurodegenerative disorderfor which the etiology and pathogenesis remain elusivealthough it is known to be a multifactorial disease involvingboth genetic and environmental factors Pedigree and cohortstudies of patients with inherited forms of PD which accountfor only 5ndash10 of cases [1] have identified numerous genesand loci associated with PD susceptibility [2 3] Autosomalrecessive mutations in six of these genes have been linkedto the disease Parkin (PARK2) [4] DJ-1 (PARK7) [5] PINK1(PARK6) [6] ATP13A2 (PARK9) [7] PLA2G6 (PARK14) [8]and FBXO7 (PARK15) [9]
Autosomal recessivemutations in theATP13A2 gene werefirst discovered in 2006 in a single Chilean pedigree [7]Several members of the family showed a rare juvenile-onsetlevodopa-responsive type of Parkinsonism named Kufor-Rakeb syndrome (KRS) involving pyramidal degenerationsupranuclear palsy and cognitive impairment Subsequent
studies in several other countries linked other mutationsto KRS and early-onset Parkinsonism At the same timeATP13A2mutations have been associatedwith the occurrenceof neurodegenerative disorders called neuronal ceroid lipo-fuscinoses (NCLs) in patients with Parkinsonism [10] Someof the NCL-associated mutations overlap with PD-associatedones suggesting a common pathway in the two types ofneurological disease
Here we review recent advances in the emerging associ-ation of ATP13A2 mutations with Parkinsonism and NCLsThese findings point to the gene andor protein as a potentialtherapeutic target
2 ATP13A2 Mutations and PD
In the first study linking ATP13A2mutations to PD pedigreeanalysis of one Chilean family with several members withKRS led to the identification of two loss-of-function muta-tions c1306+5GgtA in exon 13 and 3057delC1019GfsX1021
Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 371256 9 pageshttpdxdoiorg1011552014371256
2 BioMed Research International
in exon 26 [7] In the same study the authors also performedpedigree analysis of a Jordanian family with several memberswith KRS leading to the identification of a 22-bp duplicationin exon 16 (1632 1653dup22 or 552LfsX788) This duplicationcauses a frameshift resulting in 236 extraneous amino acidsfollowed by a stop codon All these mutations were absent ina control group of 480 healthy individuals
Sequencing the complete ATP13A2 coding region of 46patients with juvenile- or young-onset PD led to the identi-fication of three additional disease-associated mutations [11]c1510GgtCpGly504Arg in a Brazilian patient with sporadicPD c35CgtTpThr12Met (exon 2) in an Italian patient andc1597GgtApGly533Arg (exon 16) in another Italian patientThis was the first study to identify any mutation associatedwith sporadic early-onset PD [11] Subsequent studies inseveral countries identified additional novel ATP13A2muta-tions in patients with early-onset disease (Table 1) includingstudies on individuals from Japan [12 13] China [14ndash17]Europe [18] Iran [18 19] Pakistan [20] Afghanistan [21]Lithuania [22] Inuit communities in Greenland [23] andItaly [24]
The ATP13A2 mutation c2236GgtApAla746Thr (exon20) was identified in three ethnic Chinese individuals fromTaiwan and Singapore two of whom had late-onset PD [14]
However two subsequent studies failed to detect thismutation in patients with early- or late-onset PD frommainland China and Hong Kong [25ndash27] A third study of 65Chinese patients with early-onset PD detected the Ala746Thrmutation in two patients and four healthy controls [15] Thesame study also discovered a novel mutation associated withearly-onset disease (c3274 AgtG Gly1014Ser exon 26) Thesestudies highlight the need for more research particularlyon Chinese individuals to identify additional mutationsassociated with disease and to resolve conflicting resultsabout the Ala746Thr mutation
Studies using multiplex ligation-dependent probe ampli-fication (MLPA) to measure exon dosage in Iranian patientsfound deletion of ATP13A2 exon 2 to be associated withKRS [28] Three of the 232 affected individuals in the studycame from the same family and showed an average age ofdisease onset of 12 years Genomic rearrangements were notdetected among patients with sporadic or familial PD In factseveral studies have failed to identify associations ofATP13A2mutations with sporadic PD or non-KRS familial PD [25 29]or with late-onset PD [30] These findings highlight the needto examine ATP13A2 mutations in patients with sporadicor familial PD from a broad range of ethnicities in orderto clarify whether the mutations are associated only withjuvenile- or young-onset Parkinsonism or perhaps only withKRS
3 Clinical Characteristics of PD PatientsCarrying ATP13A2 Mutations
KRS was initially described in a family with Parkinsonism inthe Kufor-Rakeb district in Jordan affected individuals showa juvenile-onset levodopa-responsive form of PD involvingpyramidal signs dementia and supranuclear gaze palsy [31]
These symptoms are quite similar to those of pallidopyrami-dal syndrome though KRS differs in that it involves dystoniawhich is attributable to pyramidal dysfunction as well ascognitive dysfunction and supranuclear upgaze paresis [3132]
From the literature we extracted general clinical charac-teristics of 34 PD patients withATP13A2mutations (Table 2)Most patients had KRS or early-onset disease either sporadicor familial two patients had late-onset PD Slightly morepatients were male (21 567) than female (16 433) theaverage age of onset was 237 plusmn 138 years The youngestpatient was a 12-year-old Lithuanian boy who had had thedisease for 6 years before his case was published the oldestpatient was a 63-year-old Taiwanese woman Initial symp-toms were diverse and included bradykinesia dystonia gaitdisturbance mental retardation anxiety postural instabilityand rest tremor Clinical symptoms were varied and followedthe following distribution from themost to the least frequentrigidity (119899 = 37) bradykinesia (33) postural instability (29)supranuclear upgaze paresis (22) cognitive impairment (19)dystonia (17) resting tremor (17) hallucination (16) andmyoclonus (16) A uni- or bilateral Babinski sign was presentin 27 of 37 patients
Most patients were examined by computed tomography(CT) or magnetic resonance imaging (MRI) the most fre-quent significant features were an enlarged subarachnoidspace and diffuse atrophy ranging from mild to severeOnly two patients an adolescent from Pakistan [20] andan adolescent from Chile [33] showed abnormal bilateralhypointensity in the putaminal and caudate nuclei on T2lowastdiffuse MRI images The clinicians attending the Pakistanipatient were able to exclude manganese deposition as thecause of hypointensity since the patient did not experiencemanganese exposure or show chronic liver failure copperdeposition since the patient showed normal serum levels ofcopper and ceruloplasmin and the slit lamp test showed noK-F ring and calcium deposition since the patient showednormal CT results In the end the clinicians attributedthe abnormal MRI hypointensity to iron deposition Theclinicians attending the Chilean patient also attributed thehypointensity to ferritin deposits based on the absence ofhypointensity on brain CT images though they did notperform tests to exclude the possibility of deposition of othermetals [33]
By single-photon emission CT (SPECT) patient NAPO6an Italian with ATP13A2 mutation cG2629A showedspecific-to-nondisplaceable V101584010158403 binding ratios that were 75lower in the caudate and 85 lower in the putamen than thoseof healthy individuals [24] His younger brother designatedNAPO7 carried the same ATP13A2 mutation and showedmild mental retardation but no clinically obvious Parkin-sonism His V101584010158403 ratio was 40 lower than normal in thecaudate and 65 lower in the putamen consistent with thefact that mild retardation can be an initial symptom of PD [932] These results suggest that combining genotyping of PDsusceptibility genes with positron emission tomography orSPECT may improve diagnosis of early-stage PD especiallyin subclinical patients
BioMed Research International 3
Table 1 Review of the literature on ATP13A2mutations associated with Parkinsonrsquos disease
Ref Author Year Country of patient origin Mutation Notes
[7] Ramirez et al 2006 Chile Jordanc3057delC (p1019GfsX1021)c1306+5GgtA (pG399 L435del)c1632 1653dup22 (pLeu552fsX788)
[11] Di Fonzo et al 2007 Brazil Italyc1510GgtC (pGly504Arg)c35CgtT (pThr12Met)c1597GgtA (pGly533Arg)
[12] Ning et al 2008 Japan c546CgtA (pPhe182Leu)[14] Lin et al 2008 Taiwan Singapore c2236GgtA (pAla746Thr) Ethnic Chinese
[18] Djarmati et al 2009 Various European countriesc746CgtT (pAla249Val)c844AgtT (pSer282Cys)c2939GgtA (pArg980His)
Iran c1346GgtA (pArg449Gln)[20] Schneider et al 2010 Pakistan c1103 1104insGA (pThr367fsX29)[25] Fei et al 2010 China (mainland) c2236GgtA (pAla746Thr)[26] Mao et al 2010 China (mainland) c2236GgtA (pAla746Thr)[13] Funayama et al 2010 Japan c2236GgtA (pAla746Thr)[15] Chen et al 2011 Taiwan c3274AgtG (pGly1014Ser) Ethnic Chinese[21] Fong et al 2011 Lithuania c1108 1120del13 (pArg370fsX390)
[16] Park et al 2011 Various Asian countries c3176TgtG (pLeu1059Arg)c3253delC (pL1085wfsX1088)
[22] Crosiers et al 2011 Afghanistan c2742 2743delTT (pF851CfsX856)[23] Eiberg et al 2012 Greenland c2473CgtAA (pLeu825fs) Ethnic Inuits[17] Zhu et al 2012 China (mainland) c1754GgtT (p Ala585Asp) Ethnic Chinese[24] Santoro et al 2011 Italy c2629GgtA (pGly877Arg)[27] Chan et al 2013 China (Hong Kong) c2236GgtA (pAla746Thr) Ethnic Chinese[28] Darvish et al 2013 Iran Deletion of exon 2[19] Malakouti-Nejad et al 2014 Iran c2762CgtT (pGln858lowast)
4 Physiological Role of ATP13A2 andLink to PD
41 ATP13A2 and Function of Lysosomes and Mitochon-dria ATP13A2 encodes a lysosomal transmembrane proteinbelonging to the 5P-type ATPase subfamily [34] Wild-typeATP13A2 localizes to the lysosome while all mutant formsassociated with PD localize to the endoplasmic reticulum(ER) [9 16 35 36] In contrast to genes for other 5P-type ATPases ATP13A2 in mice is expressed mainly in thebrain suggesting a brain-specific function ATP13A2 levelsin the substantia nigra are substantially lower in postmortemtissue biopsies of patients with sporadic PD than in thecorresponding samples from healthy controls [37 38] butthey are higher in survival dopaminergic (DA) neuronsof patients than in those of controls [37] ATP13A2 levelsare particularly high in the cytosol of nigral dopaminergicneurons where the protein accumulates in Lewy bodies [37]
These circumstantial data implicate ATP13A2 in thepathogenesis andor progression of PD but more directevidence requires insights into the function of the ATP13A2protein Studies with cultures of fibroblast cells and DA cellstaken from PD patients with ATP13A2 mutations showed
that inhibiting ATP13A2 function decreased the ability oflysosomes to degrade proteins and mediate clearance ofautophagosomes [37] These cellular functions returned tonear-normal levels afterATP13A2 activity was restoredTheseresults suggest that ATP13A2 is required for normal lysosomefunctionwhich is in turn required for preventing120572-synucleinaggregation in neurons (Figure 1(a)) This aggregation is apathological hallmark of both sporadic and familial PD [39]
Several additional studies provide further evidencethat ATP13A2 prevents 120572-synuclein aggregation SH-SY5Y cultures overexpressing ATP13A2 showed lowerintracellular levels of 120572-synuclein perhaps because ofincreased 120572-synuclein export via multivesicular bodies(MVBs) (Figure 1(a)) [40] In both whole-animal andneuronal culture models of PD coexpressing ATP13A2 with120572-synuclein led to lower synuclein levels in DA neurons thanexpressing synuclein alone [41] Neuronal cultures lackingthe ATP13A2 gene showed significantly higher endogenouslevels of 120572-synuclein than did the corresponding wild-typeneurons [42] Intriguingly the ATP13A2-knockout neuronsdid not show elevated levels or aggregates of tau proteinwhich may play an important role in the pathogenesis ofAlzheimerrsquos disease (AD) This raises the possibility that
4 BioMed Research International
Table2Clinicalfeatures
ofpatie
ntsw
ithParkinsonrsquos
diseasea
ndmutations
intheA
TP13A2
gene
Ref
Internalcode
Mutation
Cou
ntry
oforigin
AO(years)
GFH
ISMS
MC
SUP
DYS
CDH
BSRe
spon
seto
levodo
paIm
agingfin
ding
s
[26]
V44
1632
1653du
p22(552LeufsX
788)
Jordan
12M
+B
MR
RB
RPI
++minus
++
++
Diffusea
troph
y(M
RI)
V48
Jordan
15M
+B
RB
RPI
++
++
++
+Diffusea
troph
y(M
RI)
V49
Jordan
13M
+MR
RB
RPI
+minus
++
++
+Diffusea
troph
y(M
RI)
V53
Jordan
12F
+B
BR
PI+minus
++
++
+NR
[1]
II-8
c3057delC(p10
19GfsX1021)
c1306+
5GgtA(pG399L4
35del)
Chile
18M
+BR
FTB
R+
+NR
++
+Never
tried
Enlarged
sulci(CT
)
II-9
Chile
17M
+BR
BR
TB
RPI
+minus
NR
++minus
minusMild
diffusea
troph
ycaud
ate
hypo
intensity
(MRI)
II-10
Chile
15F
+B
FBR
TB
RPI
++
NR
+minus
+minus
NR
II-11
Chile
12M
+FBR
TB
RPI
++
NR
++
+minus
Diffusea
troph
y(C
T)
[11]
BR-304
2c1510GgtC(G
ly504A
rg)
Brazil
12Mminus
BB
RPI
++
NR
++
++
Diffusea
troph
y(C
T)VE2
9c3
5CgtT(Th
r12M
et)
Italy
30M
+NA
TB
RPI
NR
++minusminus
++
NR
PK-69-1
c1597CgtA(G
ly533A
rg)
Italy
40M
+NA
BR
PINR
++minus
++
+NR
[18]
L-1349
c746
CgtT(A
la249V
al)
Germany
31Fminus
TTB
RPI
NR
+minus
NR
+minus
+Normal(M
RI)
L-1928
c844
AgtT(Ser282C
ys)
Norway
20Mminus
PIR
PINR
+minus
NRminus
++
Normal(M
RI)
L-324
c1346GgtA(A
rg44
9Gln)
Iran
36Mminus
TB
RPI
NR
+minus
NR
++
+Cerebralatro
phy(C
T)P-55
c2939GgtA(A
rg980H
is)Serbia
35Fminus
PTTB
RPI
NR
+minus
NR
++
+Normal
[20]
NR
c11031104
insG
A(pTh
r367fsX2
9)Pakista
n16
Mminus
BMR
BR
PIminus
++
++
++
Diffusea
troph
y(M
RI)
[22]
II-3
c27422743delTT(pF851C
fsX8
56)
Afghanista
n10
Mminus
BMR
BR
PI+
++
+minus
++
Diffusea
troph
ybilateralhypo
intensity
inpu
taminaa
ndcaud
aten
uclei(MRI)
[21]
NR
c11081120del13
(pArg370fsX
390)
Lithuania
6Mminus
Dysarthria
DYS
TB
RPI
NRminus
+minus
NRminus
+Normal(M
RI)
[23]
VI-1
c2473CgtAA(pLeu825AsnfsX3
2)
Greenland
27F
+FA
NR
NR
NR
NR
++
+NR
Diffusea
troph
y(M
RI)
VI-6
Greenland
24M
+Weakn
ess
NR
NR
NR
++
++
NR
Diffusea
troph
y(M
RI)
V-1
Greenland
12M
+T
BR
++
++
++
NR
Normal(M
RI)
V-3
Greenland
10F
+CD
TB
Rminusminusminusminus
+minus
NR
NR
V-5
Greenland
29F
+GD
PI+
+minus
+minus
+NR
Diffusea
troph
y(M
RI)
V-9
Greenland
15F
+B
MR
TB
R+
NR
NR
+minus
NR
NR
NR
[19]
X4015
c2762CgtT(pGln858lowast
)Iran
14F
+Motor
defect
TB
RPI
NR
++
+minus
++
Diffusea
troph
y(M
RI)
X404
1Iran
10M
+B
TB
RPI
NR
++
+minus
++
Diffusea
troph
y(M
RI)
R104
2Iran
30M
+NR
TB
RPI
NR
NR
NR
NR
NR
NR
+NR
[24]
NAPO
6c2
629GgtA(G
ly877A
rg)
Italy
10Mminus
GD
BR
PI+
++
+minus
++
Diffusea
troph
y(M
RI)
[12]
Ac5
46Cgt
A(Phe182L
eu)
Japan
22Fminus
GD
TB
RPI
++
++
++
+Diffusea
troph
y(M
RI)
[14]
F37
c2236GgtA(A
la746Th
r)Ch
ina
53Fminus
NA
TB
Rminusminus
+minus
NR
++
Normal(M
RI)
EK1
China
50Mminus
NA
TB
RPIminusminus
+minus
NR
++
Normal(M
RI)
Y56
China
39Mminus
NA
TB
RPIminusminus
+minus
NR
++
Normal(M
RI)
[15]
H1288
c3274AgtG(pGly1014Ser)
China
48Fminus
NA
TB
RPI
NR
NR
NR
NR
NR
NR
+Normal(M
RI)
H496
c2236GgtA(A
la746Th
r)Ch
ina
49Mminus
NA
TB
RPI
NR
NR
NR
NR
NR
NR
+NR
H2120
c2236GgtA(A
la746Th
r)Ch
ina
51Fminus
NA
TB
RPI
NR
NR
NR
NR
NR
NR
+NR
[16]
NR
c3176CgtG(Leu1059Arg)
c3253delC(L1085wfsX1088)
China
17M
+A
BR
++
+NRminus
++
Normal(M
RI)
NR
China
17F
+AD
BR
++
+NRminus
++
Normal(M
RI)
Aanx
ietyA
Oage
ofon
setB
bradykinesiaB
SBa
binski
sign
CDcognitiv
edysfu
nctio
nDd
epression
DYS
dystoniaF
femaleFA
fatigueF
Hfam
ilyhisto
ryG
genderGDgaitd
isturbanceISinitia
lsymptom
Mm
aleMC
myoclo
nusMSmotor
symptom
NR
notreportedPIposturalinstabilityPT
posturaltremorR
rigidity
SUP
supranuclear
upgaze
palsy
Ttremor
BioMed Research International 5
ATP13A2 ProteaseX
CD63120572-Synuclein
Exosome
Degradation
LysosomeX XXXX
XXXXX
XXXX
MVBsAutophagosome
Intracellular
Externalisation
Extracellular
(a)
ATP13A2++ ATP13A2minusminus
ATP ATP
Degeneration
Mitochondria
ATPATP
Ca2+
ROS
(b)
Figure 1 Model of how ATP13A2 expression may affect lysosomes and mitochondria to prevent neurodegeneration (a) After 120572-synucleinhas been internalized by autophagosomes it can be immediately degraded in lysosomes containing ATP13A2 or secreted out of the cell viamultivesicular bodies (MVBs) also containing ATP13A2 Both routes prevent intracellular accumulation of 120572-synuclein (b) Knocking outATP13A2 expression in neurons leads to mitochondrial defects resulting in higher intracellular levels of reactive oxygen species (ROS) andCa2+ both of which contribute to neurodegeneration
ATP13A2 interacts preferentially with 120572-synuclein consistentwith a recent study showing that ATP13A2 colocalized with120572-synuclein in Lewy bodies but not with 120573-amyloid [38]
In addition to ensuring proper lysosomal functionATP13A2 may work in mitochondria such that the reducedactivity of ATP13A2 mutants may lead to mitochondrialdefects that contribute to neurodegeneration (Figure 1(b))[43] Fibroblasts from patients with KRS showed lowermitochondrial membrane potential and ATP synthesis ratesthan fibroblasts from healthy individuals [33] Cell culturesdeficient in ATP13A2 showed lower levels of autophagythan healthy cells leading to higher levels of reactiveoxygen species and concomitant oxidative stress [44]
Overexpressing ATP13A2 in neurons inhibited cadmium-induced mitochondrial fragmentation while silencingATP13A2 expression induced mitochondrial fragmentation[45] (Figure 1(b)) That same study further showed thatincreasing or decreasing ATP13A2 expression substantiallyshortened the neurites of primary midbrain DA neuronswithout affecting neurites of cortical neurons This maymean that the morphological and functional integrity of DAneurons depends on well-controlled ATP13A2 expression[45]
The available evidence suggests that ATP13A2 by sup-porting lysosomal andmitochondrial function helps preventthe 120572-synuclein aggregation associated with Parkinsonism
6 BioMed Research International
[46ndash49] The implication is that the ATP13A2 mutationslinked to KRS and other forms of PD are loss-of-functionmutations that reduce ATP13A2 activity sufficiently to induceneurodegeneration Future studies should examine in detailthe activity localization and binding partners of thesemutant proteins
42 ATP13A2 and Cation Accumulation ATP13A2 plays acritical role in the transmembrane transport of manganeseand zinc and perhaps of iron and cadmium as well [15]abnormal accumulation of any of these cations can causeneurodegeneration [41 50ndash52] Thus patients with PD havebeen reported to show elevated levels of manganese and zincin serum and cerebrospinal fluid [53ndash55] andmanganese andzinc exposure are significant environmental risk factors forPD [56 57] ATP13A2 helps protect cells from this toxicity byregulating the homeostasis ofmanganese and zinc in neurons[41 44 58 59] It may be that dysregulation of ATP13A2expression disrupts the homeostasis of manganese and zincin the brain leading to neurodegeneration
This possibility is consistent with the interpretation of theabnormal hypointensity in the putamina and caudate nucleiof patients with KRS in T2lowast diffuse MRI images as irondeposits (see Section 3) This finding led those authors topropose KRS with iron deposits as a distinct condition calledneurodegeneration with brain iron accumulation (NBIA)[20] Indeed iron accumulation was reported in the substan-tia nigra of PD patients [60] where it was particularly abun-dant in DA neurons [61] Administering the iron chelatordeferiprone to an animal model of PD induced by oxidativestress improved motor function and increased dopaminelevels in the striatum [62] In a pilot randomized clinical trialdouble-blind and placebo-controlled deferiprone showedsome ability to delay or reverse the progression of PD [62]
How mutations in ATP13A2may affect cation depositionis unclear We speculate that loss-of-function mutations inATP13A2 may work similarly to silencing of the PANK2gene which disrupts normal cation transfer and leads tomitochondrial and lysosomal dysfunction and ultimatelyto cation accumulation in the brain [63 64] In this wayATP13A2mutants may trigger deposition of the cations zincmanganese and iron leading to metal-induced oxidativedamage and ultimately causing decreases in glutathione per-oxidase activity glutathione (GSH) levels andmitochondrialComplex I activity as well as increases in levels of basal lipidperoxidation free radicals and glutamate [65ndash67] The netresult is significant neuronal loss that is the distinguishingpathological feature of PD
This proposed mechanism implies that regulating orrestoring the homeostasis of neurotoxic cations may be aneuroprotective therapy for patients with PD However onlytwo of the 37 PD patients with ATP13A2 mutations that wereviewed showed cation accumulation on T2lowast diffuse MRIimages (Table 2) and direct postmortem pathological evi-dence for metal accumulation in PD is lacking [20 33] Fur-ther studies are urgently needed to clarify whether ATP13A2mutations contribute to PD by increasing susceptibility tocation toxicity
5 ATP13A2 Mutations A Link betweenParkinsonism and NCLs
ATP13A2mutations have been identified not only in patientswith Parkinsonism but also in patients with neuronal ceroidlipofuscinoses (NCLs) [10] NCLs are a group of neurode-generative disorders that are also lysosomal storage diseasesClinical manifestations are seizures progressive cognitiveand motor decline and failing vision The pathologicalhallmark of NCLs is accumulation of autofluorescent lipopig-ment within neuronal lysosomes [68]
Recently the mutation c2429CgtG in exon 22 ofATP13A2 predicted to result in the amino acid substitutionpMet810Arg was identified in a Belgian family withNCLs [10] Affected individuals showed not only typicalNCL symptoms but also extrapyramidal involvementPostmortem pathological examination revealed extensivelipofuscin deposits in the cortex basal nuclei cerebellumand retinamdashbut not the white mattermdashand electronmicroscopy showed whorled lamellar inclusions typical ofNCLs [10] A link between ATP13A2 mutations and NCLpathogenesis is further supported by studies in animalmodels [69 70] In fact mice deficient in ATP13A2 exhibitedneuronal ceroid lipofuscinosis 120572-synuclein accumulationand age-dependent sensorimotor deficits suggesting that PDand NCLs share a pathogenic mechanism [71]
A shared disease pathwaymay help explain earlier reportsof individuals who demonstrate an ldquooverlappingrdquo neurode-generative syndrome combining Parkinsonism and NCLs[72ndash76] ATP13A2 is a lysosomal transport protein that helpsmaintain optimal pH in lysosomes [46] and ceramide ismetabolized in lysosomes [77] The apoptosis that appears tocause NCLs is associated with increased levels of ceramide[78 79] which have also been linked to 120572-synuclein deposi-tion whichmay contribute to PDpathogenesis [80] Itmay bethat ATP13A2 helps regulate ceramide metabolism such thatsignificant changes in ATP13A2 activitymay contribute to thepathogenesis of both PD and NCLs This model is similar tothat of the lysosomal storage disorder called Gaucher diseaseThe homozygousmutations in the 120573-glucocerebrosidase genethat cause Gaucher disease also increase risk of PD [81]Both diseases arise because lysosomal dysfunction leadsto excessive aggregation of substrates that normally aredegraded Analogously lysosomal dysfunction may underliethe clinically different neurodegenerative disorders of PD andNCLs
6 Summary
Much has been learned about the physiological functionsof ATP13A2 since mutations in the ATP13A2 gene werefirst linked to autosomal recessive familial KRS [7] Patientswith such mutations show onset at earlier ages than patientswith other forms of PD as well as some atypical clinicalsymptoms such as pyramidal degeneration supranuclearpalsy cognitive impairment and dystonia Studies in animalmodels of PD and in cultures of cells taken from patients withKRS and other types of PD suggest that ATP13A2 is important
BioMed Research International 7
for proper functioning of lysosomes and mitochondria andperhaps for clearance of divalent metals defects in any ofthese three processes are tightly associated with neurodegen-eration Nevertheless more studies are needed that directlyexamine how PD-associated mutations in ATP13A2 affectthe activity and localization of the protein and ultimatelythe integrity of these three processes ATP13A2 mutationsthat affect one of these processes lysosomal functioningmay simultaneously increase the risk of PD and NCLs Inotherwords these quite clinically different diseasesmay sharea mechanism of lysosomal dysfunction If further studiesvalidate the literature the ATP13A2 gene andor protein maybecome a suitable therapeutic target for treating both PD andNCLs
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Work by the authors related to this review was supportedby the Sichuan Key Project of Science and Technology (no2010SZ0086) and the National Natural Science Foundationof China (no 30700243)
References
[1] S Lesage and A Brice ldquoParkinsonrsquos disease from monogenicforms to genetic susceptibility factorsrdquo Human MolecularGenetics vol 18 no R1 pp R48ndashR59 2009
[2] V Bonifati ldquoGenetics of Parkinsonrsquos diseasemdashstate of the artrdquoParkinsonism amp Related Disorders vol 20 supplement 1 ppS23ndashS28 2014
[3] F Coppede ldquoGenetics and epigenetics of Parkinsonrsquos diseaserdquoScientific World Journal vol 2012 Article ID 489830 12 pages2012
[4] S Lesage E Lohmann F Tison F Durif A Durr and ABrice ldquoGene symbol PARK2 Disease parkinsonism juvenileautosomal recessiverdquoHuman genetics vol 123 no 1 article 1142008
[5] V Bonifati P Rizzu M J Van Baren et al ldquoMutations inthe DJ-1 gene associated with autosomal recessive early-onsetparkinsonismrdquo Science vol 299 no 5604 pp 256ndash259 2003
[6] Y Li H Tomiyama K Sato et al ldquoClinicogenetic study ofPINK1mutations in autosomal recessive early-onset parkinson-ismrdquo Neurology vol 64 no 11 pp 1955ndash1957 2005
[7] A Ramirez A Heimbach J Grundemann et al ldquoHeredi-tary parkinsonism with dementia is caused by mutations inATP13A2 encoding a lysosomal type 5 P-type ATPaserdquo NatureGenetics vol 38 no 10 pp 1184ndash1191 2006
[8] H Tomiyama H Yoshino K Ogaki et al ldquoPLA2G6 variant inParkinsons diseaserdquo Journal of Human Genetics vol 56 no 5pp 401ndash403 2011
[9] A Di Fonzo M C J Dekker P Montagna et al ldquoFBXO7mutations cause autosomal recessive early-onset parkinsonian-pyramidal syndromerdquo Neurology vol 72 no 3 pp 240ndash2452009
[10] J Bras A Verloes S A Schneider S E Mole and R J Guer-reiro ldquoMutation of the parkinsonism gene ATP13A2 causesneuronal ceroid-lipofuscinosisrdquo Human Molecular Geneticsvol 21 no 12 pp 2646ndash2650 2012
[11] A Di Fonzo H F Chien M Socal et al ldquoATP13A2 missensemutations in juvenile Parkinsonism and young onset Parkinsondiseaserdquo Neurology vol 68 no 19 pp 1557ndash1562 2007
[12] Y P Ning K Kanai H Tomiyama et al ldquoPARK9-linkedparkinsonism in eastern Asia mutation detection in ATP13A2and clinical phenotyperdquo Neurology vol 70 no 16 part 2 pp1491ndash1493 2008
[13] M Funayama H Tomiyama R M Wu et al ldquoRapid screeningof ATP13A2 variant with highresolution melting analysisrdquoMovement Disorders vol 25 no 14 pp 2434ndash2437 2010
[14] C H Lin E K Tan M L Chen et al ldquoNovel ATP13A2 variantassociated with Parkinson disease in Taiwan and SingaporerdquoNeurology vol 71 no 21 pp 1727ndash1732 2008
[15] C-M Chen C-H Lin H-F Juan et al ldquoATP13A2 variabilityin Taiwanese Parkinsonrsquos diseaserdquo American Journal of MedicalGenetics B Neuropsychiatric Genetics vol 156 no 6 pp 720ndash729 2011
[16] J Park PMehta A A Cooper et al ldquoPathogenic effects of novelmutations in the P-type ATPase ATP13A2 (PARK9) causingKufor-Rakeb syndrome a form of early-onset parkinsonismrdquoHuman Mutation vol 32 no 8 pp 956ndash964 2011
[17] L H Zhu X G Luo Y S Zhou et al ldquoLack of associationbetween three single nucleotide polymorphisms in the PARK9PARK15 and BST1 genes and Parkinsonrsquos disease in the north-ern Han Chinese populationrdquo Chinese Medical Journal vol 125no 4 pp 588ndash592 2012
[18] A Djarmati J Hagenah K Reetz et al ldquoATP13A2 variants inearly-onset Parkinsonrsquos disease patients and controlsrdquo Move-ment Disorders vol 24 no 14 pp 2104ndash2111 2009
[19] M Malakouti-Nejad G A Shahidi M Rohani et al ldquoIdenti-fication of pGln858lowast in ATP13A2 in two EOPD patients andpresentation of their clinical featuresrdquoNeuroscience Letters vol577 pp 106ndash111 2014
[20] S A Schneider C Paisan-Ruiz N P Quinn et al ldquoATP13A2mutations (PARK9) cause neurodegeneration with brain ironaccumulationrdquoMovement Disorders vol 25 no 8 pp 979ndash9842010
[21] C Y Fong A Rolfs T Schwarzbraun C Klein and F J KOrsquoCallaghan ldquoJuvenile parkinsonism associated with heterozy-gous frameshift ATP13A2 gene mutationrdquo European Journal ofPaediatric Neurology vol 15 no 3 pp 271ndash275 2011
[22] D Crosiers B Ceulemans B Meeus et al ldquoJuvenile dystonia-parkinsonism and dementia caused by a novel ATP13A2frameshift mutationrdquo Parkinsonism and Related Disorders vol17 no 2 pp 135ndash138 2011
[23] H Eiberg L Hansen L Korbo et al ldquoNovel mutation inATP13A2 widens the spectrum of Kufor-Rakeb syndrome(PARK9)rdquo Clinical Genetics vol 82 no 3 pp 256ndash263 2012
[24] L Santoro G J Breedveld F Manganelli et al ldquoNovelATP13A2(PARK9) homozygous mutation in a family with markedphenotype variabilityrdquo Neurogenetics vol 12 no 1 pp 33ndash392011
[25] Q Z Fei L Cao Q Xiao et al ldquoLack of association betweenATP13A2 Ala746Thr variant and Parkinsons disease in Hanpopulation of mainland Chinardquo Neuroscience Letters vol 475no 2 pp 61ndash63 2010
8 BioMed Research International
[26] X Y Mao J M Burgunder Z J Zhang et al ldquoATP13A2G2236A variant is rare in patients with early-onset Parkinsonrsquosdisease and familial Parkinsonrsquos disease from mainland ChinardquoParkinsonism and Related Disorders vol 16 no 3 pp 235ndash2362010
[27] A Y Y Chan L Baum N L S Tang et al ldquoThe role ofthe Ala746Thr variant in the ATP13A2 gene among Chinesepatients with Parkinsonrsquos diseaserdquo Journal of Clinical Neuro-science vol 20 no 5 pp 761ndash762 2013
[28] H Darvish A Movafagh M D Omrani et al ldquoDetectionof copy number changes in genes associated with Parkinsonrsquosdisease in Iranian patientsrdquo Neuroscience Letters vol 551 pp75ndash78 2013
[29] C Vilarino-Guell A I Soto S J Lincoln et al ldquoATP13A2variability in Parkinson diseaserdquo Human Mutation vol 30 no3 pp 406ndash410 2009
[30] A Rakovic B Stiller A Djarmati et al ldquoGenetic associationstudy of the P-type ATPase ATP13A2 in late-onset ParkinsonrsquosdiseaserdquoMovement Disorders vol 24 no 3 pp 429ndash433 2009
[31] A S Najim Al-Din A Wriekat A Mubaidin M Dasoukiand M Hiari ldquoPallido-pyramidal degeneration supranuclearupgaze paresis and dementia Kufor-Rakeb syndromerdquo ActaNeurologica Scandinavica vol 89 no 5 pp 347ndash352 1994
[32] D R Williams A Hadeed A S Najim al-Din A Wreikatand A J Lees ldquoKufor Rakeb disease autosomal recessivelevodopa-responsive Parkinsonism with pyramidal degenera-tion supranuclear gaze palsy and dementiardquoMovement Disor-ders vol 20 no 10 pp 1264ndash1271 2005
[33] M I Behrens N Bruggemann P Chana et al ldquoClinicalspectrum of Kufor-Rakeb syndrome in the Chilean kindredwith ATP13A2 mutationsrdquoMovement Disorders vol 25 no 12pp 1929ndash1937 2010
[34] P J Schultheis T T Hagen K K OrsquoToole et al ldquoCharacteriza-tion of the P5 subfamily of P-type transport ATPases in micerdquoBiochemical and Biophysical Research Communications vol 323no 3 pp 731ndash738 2004
[35] B Schroder CWrocklage C Pan et al ldquoIntegral and associatedlysosomal membrane proteinsrdquo Traffic vol 8 no 12 pp 1676ndash1686 2007
[36] H Matsui F Sato S Sato et al ldquoATP13A2 deficiency inducesa decrease in cathepsin D activity fingerprint-like inclusionbody formation and selective degeneration of dopaminergicneuronsrdquo FEBS Letters vol 587 no 9 pp 1316ndash1325 2013
[37] B Dehay A Ramirez M Martinez-Vicente et al ldquoLoss of P-type ATPase ATP13A2PARK9 function induces general lyso-somal deficiency and leads to Parkinson disease neurodegen-erationrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 109 no 24 pp 9611ndash9616 2012
[38] K E Murphy L Cottle A M Gysbers A A Cooper and GM Halliday ldquoATP13A2 (PARK9) protein levels are reduced inbrain tissue of cases with Lewy bodiesrdquo Acta NeuropathologicaCommunications vol 1 article 11 2013
[39] G K Tofaris ldquoLysosome-dependent pathways as a unifyingtheme in Parkinsonrsquos diseaserdquo Movement Disorders vol 27 no11 pp 1364ndash1369 2012
[40] S M Kong B K Chan J S Park et al ldquoParkinsonrsquos disease-linked human PARK9 ATP13A2 maintains zinc homeosta-sis and promotes 120572-Synuclein externalization via exosomesrdquoHuman Molecular Genetics vol 23 no 11 pp 2816ndash2833 2014
[41] A D Gitler A Chesi M L Geddie et al ldquo120572-Synuclein ispart of a diverse and highly conserved interaction network that
includes PARK9 and manganese toxicityrdquo Nature Genetics vol41 no 3 pp 308ndash315 2009
[42] M Usenovic E Tresse J R Mazzulli J P Taylor and DKrainc ldquoDeficiency ofATP13A2 leads to lysosomal dysfunction120572-synuclein accumulation and neurotoxicityrdquo The Journal ofNeuroscience vol 32 no 12 pp 4240ndash4246 2012
[43] J S Park B Koentjoro D Veivers A Mackay-Sim and C MSue ldquoParkinsonrsquos disease-associated human ATP13A2 (PARK9)deficiency causes zinc dyshomeostasis andmitochondrial dys-functionrdquo Human Molecular Genetics vol 23 no 11 pp 2802ndash2815 2014
[44] A M Gusdon J Zhu B van Houten and C T ChuldquoATP13A2 regulates mitochondrial bioenergetics throughmacroautophagyrdquo Neurobiology of Disease vol 45 no 3 pp962ndash972 2012
[45] D Ramonet A Podhajska K Stafa et al ldquoPARK9-associatedATP13A2 localizes to intracellular acidic vesicles and regulatescation homeostasis and neuronal integrityrdquo Human MolecularGenetics vol 21 no 8 pp 1725ndash1743 2012
[46] R A Nixon D S Yang and J H Lee ldquoNeurodegenerativelysosomal disorders a continuum from development to lateagerdquo Autophagy vol 4 no 5 pp 590ndash599 2008
[47] B Dehay M Martinez-Vicente G A Caldwell et al ldquoLysoso-mal impairment in Parkinsonrsquos diseaserdquo Movement Disordersvol 28 no 6 pp 725ndash732 2013
[48] C W Olanow and P Brundin ldquoParkinsonrsquos disease and alphasynuclein is Parkinsonrsquos disease a prion-like disorderrdquo Move-ment Disorders vol 28 no 1 pp 31ndash40 2013
[49] J Bove M Martınez-Vicente and M Vila ldquoFighting neu-rodegeneration with rapamycin mechanistic insightsrdquo NatureReviews Neuroscience vol 12 no 8 pp 437ndash452 2011
[50] K Schmidt D M Wolfe B Stiller and D A Pearce ldquoCd2+Mn2+ Ni2+ and Se2+ toxicity to Saccharomyces cerevisiaelacking YPK9p the orthologue of human ATP13A2rdquo Biochem-ical and Biophysical Research Communications vol 383 no 2pp 198ndash202 2009
[51] P G Mastroberardino E K Hoffman M P Horowitz et al ldquoAnovel transferrinTfR2-mediated mitochondrial iron transportsystem is disrupted in Parkinsonrsquos diseaserdquo Neurobiology ofDisease vol 34 no 3 pp 417ndash431 2009
[52] C T Sheline J Zhu W Zhang C Shi and A Cai ldquoMitochon-drial inhibitor models of Huntingtonrsquos disease and Parkinsonrsquosdisease induce zinc accumulation and are attenuated by inhibi-tion of zinc neurotoxicity in vitro or in vivordquoNeurodegenerativeDiseases vol 11 no 1 pp 49ndash58 2013
[53] T Fukushima X Tan Y Luo and H Kanda ldquoSerum vitaminsand heavy metals in blood and urine and the correlationsamong them in parkinsonrsquos disease patients inChinardquoNeuroepi-demiology vol 36 no 4 pp 240ndash244 2011
[54] I Hozumi T Hasegawa A Honda et al ldquoPatterns of levelsof biological metals in CSF differ among neurodegenerativediseasesrdquo Journal of the Neurological Sciences vol 303 no 1-2pp 95ndash99 2011
[55] F J Jimenez-Jimenez P Fernandez-Calle M Martınez-Vanaclocha et al ldquoSerum levels of zinc and copper in patientswith Parkinsonrsquos diseaserdquo Journal of the Neurological Sciencesvol 112 no 1-2 pp 30ndash33 1992
[56] T R Guilarte ldquoManganese and Parkinsonrsquos disease a criticalreview and new findingsrdquo Environmental Health Perspectivesvol 118 no 8 pp 1071ndash1080 2010
BioMed Research International 9
[57] P Pals B van Everbroeck B Grubben et al ldquoCase-controlstudy of environmental risk factors for Parkinsonrsquos disease inBelgiumrdquo European Journal of Epidemiology vol 18 no 12 pp1133ndash1142 2003
[58] G Rentschler L Covolo A Ahmadi Haddad R G LucchiniS Zoni and K Broberg ldquoATP13A2 (PARK9) polymorphismsinfluence the neurotoxic effects of manganeserdquo NeuroToxicol-ogy vol 33 no 4 pp 697ndash702 2012
[59] J Tan T Zhang L Jiang et al ldquoRegulation of intracellularmanganese homeostasis by Kufor-Rakeb syndrome-associatedATP13A2 proteinrdquo Journal of Biological Chemistry vol 286 no34 pp 29654ndash29662 2011
[60] D Berg andHHochstrasser ldquoIronmetabolism in parkinsoniansyndromesrdquo Movement Disorders vol 21 no 9 pp 1299ndash13102006
[61] A E Oakley J F Collingwood J Dobson et al ldquoIndividualdopaminergic neurons show raised iron levels in Parkinsondiseaserdquo Neurology vol 68 no 21 pp 1820ndash1825 2007
[62] D Devos C Moreau and J C Devedjian ldquoTargeting chelatableiron as a therapeutic modality in Parkinsonrsquos diseaserdquo Antioxi-dants and Redox Signaling vol 21 no 2 pp 195ndash210 2014
[63] M Poli M Derosas S Luscieti et al ldquoPantothenate kinase-2 (Pank2) silencing causes cell growth reduction cell-specificferroportin upregulation and iron deregulationrdquo Neurobiologyof Disease vol 39 no 2 pp 204ndash210 2010
[64] T Tsunemi and D Krainc ldquoZn2+ dyshomeostasis caused by lossof ATP13A2PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulationrdquo Human Molecular Genetics vol 23no 11 pp 2791ndash2801 2014
[65] J Xu E Marzetti A Y Seo J Kim T A Prolla and CLeeuwenburgh ldquoThe emerging role of iron dyshomeostasis inthe mitochondrial decay of agingrdquo Mechanisms of Ageing andDevelopment vol 131 no 7-8 pp 487ndash493 2010
[66] M B H Youdim and P Riederer ldquoThe role of iron in senescenceof dopaminergic neurons in Parkinsonrsquos diseaserdquo Journal ofNeural Transmission Supplement no 40 pp 57ndash67 1993
[67] P Karki E Lee and M Aschner ldquoManganese neurotoxicity afocus on glutamate transportersrdquo Annals of Occupational andEnvironmental Medicine vol 25 no 1 article 4 2013
[68] H H Goebel L Gerhard E Kominami and M Hal-tia ldquoNeuronal ceroid-lipofuscinosismdashlate-infantile or Jansky-Bielschowsky typemdashrevisitedrdquo Brain Pathology vol 6 no 3 pp225ndash228 1996
[69] A Wohlke U Philipp P Bock et al ldquoA one base pair deletionin the canine ATP13A2 gene causes exon skipping and late-onset neuronal ceroid lipofuscinosis in the Tibetan terrierrdquoPLoS Genetics vol 7 no 10 Article ID e1002304 2011
[70] F H G Farias R Zeng G S Johnson et al ldquoA truncatingmuta-tion in ATP13A2 is responsible for adult-onset neuronal ceroidlipofuscinosis in Tibetan terriersrdquo Neurobiology of Disease vol42 no 3 pp 468ndash474 2011
[71] P J Schultheis S M Fleming A K Clippinger et al ldquoAtp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis limited120572-synuclein accumulation and age-dependent sensorimotordeficitsrdquo Human Molecular Genetics vol 22 no 10 pp 2067ndash2082 2013
[72] J G Burneo T Arnold C A Palmer R I Kuzniecky SJ Oh and E Faught ldquoAdult-onset neuronal ceroid lipofusci-nosis (Kufs disease) with autosomal dominant inheritance inAlabamardquo Epilepsia vol 44 no 6 pp 841ndash846 2003
[73] S F Berkovic S Carpenter F Andermann E Andermann andL S Wolfe ldquoKufsrsquo disease a critical reappraisalrdquo Brain vol 111no 1 part 1 pp 27ndash62 1988
[74] P C G Nijssen E Brusse A C M Leyten J J Martin JL J M Teepen and R A C Roos ldquoAutosomal dominantadult neuronal ceroid lipofuscinosis parkinsonism due to bothstriatal and nigral dysfunctionrdquoMovement Disorders vol 17 no3 pp 482ndash487 2002
[75] P E M Taschner N de Vos A D Thompson et al ldquoChro-mosome 16 microdeletion in a patient with juvenile neuronalceroid lipofuscinosis (Batten disease)rdquoThe American Journal ofHuman Genetics vol 56 no 3 pp 663ndash668 1995
[76] A Y Lavrov E S Ilyna E Y Zakharova A M Boukina andS V Tishkanina ldquoThe first three Russian cases of classical late-infantile neuronal ceroid lipofuscinosisrdquo European Journal ofPaediatric Neurology vol 6 no 3 pp 161ndash164 2002
[77] J Bras A Singleton M R Cookson and J Hardy ldquoEmerg-ing pathways in genetic Parkinsonrsquos disease potential role ofceramide metabolism in Lewy body diseaserdquo FEBS Journal vol275 no 23 pp 5767ndash5773 2008
[78] S El Haddad M Khoury M Daoud et al ldquoCLN5 and CLN8protein association with ceramide synthase biochemical andproteomic approachesrdquoElectrophoresis vol 33 no 24 pp 3798ndash3809 2012
[79] D Persaud-Sawin T Mousallem C Wang A Zucker E Kom-inami and R N Boustany ldquoNeuronal ceroid lipofuscinosis acommon pathwayrdquo Pediatric Research vol 61 no 2 pp 146ndash152 2007
[80] T J van Ham K L Thijssen R Breitling R M W Hofstra RH A Plasterk and E A A Nollen ldquoC elegansmodel identifiesgenetic modifiers of 120572-synuclein inclusion formation duringagingrdquo PLoS Genetics vol 4 no 3 Article ID e1000027 2008
[81] A Halperin D Elstein and A Zimran ldquoIncreased incidenceof Parkinson disease among relatives of patients with Gaucherdiseaserdquo Blood Cells Molecules and Diseases vol 36 no 3 pp426ndash428 2006
Submit your manuscripts athttpwwwhindawicom
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Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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2 BioMed Research International
in exon 26 [7] In the same study the authors also performedpedigree analysis of a Jordanian family with several memberswith KRS leading to the identification of a 22-bp duplicationin exon 16 (1632 1653dup22 or 552LfsX788) This duplicationcauses a frameshift resulting in 236 extraneous amino acidsfollowed by a stop codon All these mutations were absent ina control group of 480 healthy individuals
Sequencing the complete ATP13A2 coding region of 46patients with juvenile- or young-onset PD led to the identi-fication of three additional disease-associated mutations [11]c1510GgtCpGly504Arg in a Brazilian patient with sporadicPD c35CgtTpThr12Met (exon 2) in an Italian patient andc1597GgtApGly533Arg (exon 16) in another Italian patientThis was the first study to identify any mutation associatedwith sporadic early-onset PD [11] Subsequent studies inseveral countries identified additional novel ATP13A2muta-tions in patients with early-onset disease (Table 1) includingstudies on individuals from Japan [12 13] China [14ndash17]Europe [18] Iran [18 19] Pakistan [20] Afghanistan [21]Lithuania [22] Inuit communities in Greenland [23] andItaly [24]
The ATP13A2 mutation c2236GgtApAla746Thr (exon20) was identified in three ethnic Chinese individuals fromTaiwan and Singapore two of whom had late-onset PD [14]
However two subsequent studies failed to detect thismutation in patients with early- or late-onset PD frommainland China and Hong Kong [25ndash27] A third study of 65Chinese patients with early-onset PD detected the Ala746Thrmutation in two patients and four healthy controls [15] Thesame study also discovered a novel mutation associated withearly-onset disease (c3274 AgtG Gly1014Ser exon 26) Thesestudies highlight the need for more research particularlyon Chinese individuals to identify additional mutationsassociated with disease and to resolve conflicting resultsabout the Ala746Thr mutation
Studies using multiplex ligation-dependent probe ampli-fication (MLPA) to measure exon dosage in Iranian patientsfound deletion of ATP13A2 exon 2 to be associated withKRS [28] Three of the 232 affected individuals in the studycame from the same family and showed an average age ofdisease onset of 12 years Genomic rearrangements were notdetected among patients with sporadic or familial PD In factseveral studies have failed to identify associations ofATP13A2mutations with sporadic PD or non-KRS familial PD [25 29]or with late-onset PD [30] These findings highlight the needto examine ATP13A2 mutations in patients with sporadicor familial PD from a broad range of ethnicities in orderto clarify whether the mutations are associated only withjuvenile- or young-onset Parkinsonism or perhaps only withKRS
3 Clinical Characteristics of PD PatientsCarrying ATP13A2 Mutations
KRS was initially described in a family with Parkinsonism inthe Kufor-Rakeb district in Jordan affected individuals showa juvenile-onset levodopa-responsive form of PD involvingpyramidal signs dementia and supranuclear gaze palsy [31]
These symptoms are quite similar to those of pallidopyrami-dal syndrome though KRS differs in that it involves dystoniawhich is attributable to pyramidal dysfunction as well ascognitive dysfunction and supranuclear upgaze paresis [3132]
From the literature we extracted general clinical charac-teristics of 34 PD patients withATP13A2mutations (Table 2)Most patients had KRS or early-onset disease either sporadicor familial two patients had late-onset PD Slightly morepatients were male (21 567) than female (16 433) theaverage age of onset was 237 plusmn 138 years The youngestpatient was a 12-year-old Lithuanian boy who had had thedisease for 6 years before his case was published the oldestpatient was a 63-year-old Taiwanese woman Initial symp-toms were diverse and included bradykinesia dystonia gaitdisturbance mental retardation anxiety postural instabilityand rest tremor Clinical symptoms were varied and followedthe following distribution from themost to the least frequentrigidity (119899 = 37) bradykinesia (33) postural instability (29)supranuclear upgaze paresis (22) cognitive impairment (19)dystonia (17) resting tremor (17) hallucination (16) andmyoclonus (16) A uni- or bilateral Babinski sign was presentin 27 of 37 patients
Most patients were examined by computed tomography(CT) or magnetic resonance imaging (MRI) the most fre-quent significant features were an enlarged subarachnoidspace and diffuse atrophy ranging from mild to severeOnly two patients an adolescent from Pakistan [20] andan adolescent from Chile [33] showed abnormal bilateralhypointensity in the putaminal and caudate nuclei on T2lowastdiffuse MRI images The clinicians attending the Pakistanipatient were able to exclude manganese deposition as thecause of hypointensity since the patient did not experiencemanganese exposure or show chronic liver failure copperdeposition since the patient showed normal serum levels ofcopper and ceruloplasmin and the slit lamp test showed noK-F ring and calcium deposition since the patient showednormal CT results In the end the clinicians attributedthe abnormal MRI hypointensity to iron deposition Theclinicians attending the Chilean patient also attributed thehypointensity to ferritin deposits based on the absence ofhypointensity on brain CT images though they did notperform tests to exclude the possibility of deposition of othermetals [33]
By single-photon emission CT (SPECT) patient NAPO6an Italian with ATP13A2 mutation cG2629A showedspecific-to-nondisplaceable V101584010158403 binding ratios that were 75lower in the caudate and 85 lower in the putamen than thoseof healthy individuals [24] His younger brother designatedNAPO7 carried the same ATP13A2 mutation and showedmild mental retardation but no clinically obvious Parkin-sonism His V101584010158403 ratio was 40 lower than normal in thecaudate and 65 lower in the putamen consistent with thefact that mild retardation can be an initial symptom of PD [932] These results suggest that combining genotyping of PDsusceptibility genes with positron emission tomography orSPECT may improve diagnosis of early-stage PD especiallyin subclinical patients
BioMed Research International 3
Table 1 Review of the literature on ATP13A2mutations associated with Parkinsonrsquos disease
Ref Author Year Country of patient origin Mutation Notes
[7] Ramirez et al 2006 Chile Jordanc3057delC (p1019GfsX1021)c1306+5GgtA (pG399 L435del)c1632 1653dup22 (pLeu552fsX788)
[11] Di Fonzo et al 2007 Brazil Italyc1510GgtC (pGly504Arg)c35CgtT (pThr12Met)c1597GgtA (pGly533Arg)
[12] Ning et al 2008 Japan c546CgtA (pPhe182Leu)[14] Lin et al 2008 Taiwan Singapore c2236GgtA (pAla746Thr) Ethnic Chinese
[18] Djarmati et al 2009 Various European countriesc746CgtT (pAla249Val)c844AgtT (pSer282Cys)c2939GgtA (pArg980His)
Iran c1346GgtA (pArg449Gln)[20] Schneider et al 2010 Pakistan c1103 1104insGA (pThr367fsX29)[25] Fei et al 2010 China (mainland) c2236GgtA (pAla746Thr)[26] Mao et al 2010 China (mainland) c2236GgtA (pAla746Thr)[13] Funayama et al 2010 Japan c2236GgtA (pAla746Thr)[15] Chen et al 2011 Taiwan c3274AgtG (pGly1014Ser) Ethnic Chinese[21] Fong et al 2011 Lithuania c1108 1120del13 (pArg370fsX390)
[16] Park et al 2011 Various Asian countries c3176TgtG (pLeu1059Arg)c3253delC (pL1085wfsX1088)
[22] Crosiers et al 2011 Afghanistan c2742 2743delTT (pF851CfsX856)[23] Eiberg et al 2012 Greenland c2473CgtAA (pLeu825fs) Ethnic Inuits[17] Zhu et al 2012 China (mainland) c1754GgtT (p Ala585Asp) Ethnic Chinese[24] Santoro et al 2011 Italy c2629GgtA (pGly877Arg)[27] Chan et al 2013 China (Hong Kong) c2236GgtA (pAla746Thr) Ethnic Chinese[28] Darvish et al 2013 Iran Deletion of exon 2[19] Malakouti-Nejad et al 2014 Iran c2762CgtT (pGln858lowast)
4 Physiological Role of ATP13A2 andLink to PD
41 ATP13A2 and Function of Lysosomes and Mitochon-dria ATP13A2 encodes a lysosomal transmembrane proteinbelonging to the 5P-type ATPase subfamily [34] Wild-typeATP13A2 localizes to the lysosome while all mutant formsassociated with PD localize to the endoplasmic reticulum(ER) [9 16 35 36] In contrast to genes for other 5P-type ATPases ATP13A2 in mice is expressed mainly in thebrain suggesting a brain-specific function ATP13A2 levelsin the substantia nigra are substantially lower in postmortemtissue biopsies of patients with sporadic PD than in thecorresponding samples from healthy controls [37 38] butthey are higher in survival dopaminergic (DA) neuronsof patients than in those of controls [37] ATP13A2 levelsare particularly high in the cytosol of nigral dopaminergicneurons where the protein accumulates in Lewy bodies [37]
These circumstantial data implicate ATP13A2 in thepathogenesis andor progression of PD but more directevidence requires insights into the function of the ATP13A2protein Studies with cultures of fibroblast cells and DA cellstaken from PD patients with ATP13A2 mutations showed
that inhibiting ATP13A2 function decreased the ability oflysosomes to degrade proteins and mediate clearance ofautophagosomes [37] These cellular functions returned tonear-normal levels afterATP13A2 activity was restoredTheseresults suggest that ATP13A2 is required for normal lysosomefunctionwhich is in turn required for preventing120572-synucleinaggregation in neurons (Figure 1(a)) This aggregation is apathological hallmark of both sporadic and familial PD [39]
Several additional studies provide further evidencethat ATP13A2 prevents 120572-synuclein aggregation SH-SY5Y cultures overexpressing ATP13A2 showed lowerintracellular levels of 120572-synuclein perhaps because ofincreased 120572-synuclein export via multivesicular bodies(MVBs) (Figure 1(a)) [40] In both whole-animal andneuronal culture models of PD coexpressing ATP13A2 with120572-synuclein led to lower synuclein levels in DA neurons thanexpressing synuclein alone [41] Neuronal cultures lackingthe ATP13A2 gene showed significantly higher endogenouslevels of 120572-synuclein than did the corresponding wild-typeneurons [42] Intriguingly the ATP13A2-knockout neuronsdid not show elevated levels or aggregates of tau proteinwhich may play an important role in the pathogenesis ofAlzheimerrsquos disease (AD) This raises the possibility that
4 BioMed Research International
Table2Clinicalfeatures
ofpatie
ntsw
ithParkinsonrsquos
diseasea
ndmutations
intheA
TP13A2
gene
Ref
Internalcode
Mutation
Cou
ntry
oforigin
AO(years)
GFH
ISMS
MC
SUP
DYS
CDH
BSRe
spon
seto
levodo
paIm
agingfin
ding
s
[26]
V44
1632
1653du
p22(552LeufsX
788)
Jordan
12M
+B
MR
RB
RPI
++minus
++
++
Diffusea
troph
y(M
RI)
V48
Jordan
15M
+B
RB
RPI
++
++
++
+Diffusea
troph
y(M
RI)
V49
Jordan
13M
+MR
RB
RPI
+minus
++
++
+Diffusea
troph
y(M
RI)
V53
Jordan
12F
+B
BR
PI+minus
++
++
+NR
[1]
II-8
c3057delC(p10
19GfsX1021)
c1306+
5GgtA(pG399L4
35del)
Chile
18M
+BR
FTB
R+
+NR
++
+Never
tried
Enlarged
sulci(CT
)
II-9
Chile
17M
+BR
BR
TB
RPI
+minus
NR
++minus
minusMild
diffusea
troph
ycaud
ate
hypo
intensity
(MRI)
II-10
Chile
15F
+B
FBR
TB
RPI
++
NR
+minus
+minus
NR
II-11
Chile
12M
+FBR
TB
RPI
++
NR
++
+minus
Diffusea
troph
y(C
T)
[11]
BR-304
2c1510GgtC(G
ly504A
rg)
Brazil
12Mminus
BB
RPI
++
NR
++
++
Diffusea
troph
y(C
T)VE2
9c3
5CgtT(Th
r12M
et)
Italy
30M
+NA
TB
RPI
NR
++minusminus
++
NR
PK-69-1
c1597CgtA(G
ly533A
rg)
Italy
40M
+NA
BR
PINR
++minus
++
+NR
[18]
L-1349
c746
CgtT(A
la249V
al)
Germany
31Fminus
TTB
RPI
NR
+minus
NR
+minus
+Normal(M
RI)
L-1928
c844
AgtT(Ser282C
ys)
Norway
20Mminus
PIR
PINR
+minus
NRminus
++
Normal(M
RI)
L-324
c1346GgtA(A
rg44
9Gln)
Iran
36Mminus
TB
RPI
NR
+minus
NR
++
+Cerebralatro
phy(C
T)P-55
c2939GgtA(A
rg980H
is)Serbia
35Fminus
PTTB
RPI
NR
+minus
NR
++
+Normal
[20]
NR
c11031104
insG
A(pTh
r367fsX2
9)Pakista
n16
Mminus
BMR
BR
PIminus
++
++
++
Diffusea
troph
y(M
RI)
[22]
II-3
c27422743delTT(pF851C
fsX8
56)
Afghanista
n10
Mminus
BMR
BR
PI+
++
+minus
++
Diffusea
troph
ybilateralhypo
intensity
inpu
taminaa
ndcaud
aten
uclei(MRI)
[21]
NR
c11081120del13
(pArg370fsX
390)
Lithuania
6Mminus
Dysarthria
DYS
TB
RPI
NRminus
+minus
NRminus
+Normal(M
RI)
[23]
VI-1
c2473CgtAA(pLeu825AsnfsX3
2)
Greenland
27F
+FA
NR
NR
NR
NR
++
+NR
Diffusea
troph
y(M
RI)
VI-6
Greenland
24M
+Weakn
ess
NR
NR
NR
++
++
NR
Diffusea
troph
y(M
RI)
V-1
Greenland
12M
+T
BR
++
++
++
NR
Normal(M
RI)
V-3
Greenland
10F
+CD
TB
Rminusminusminusminus
+minus
NR
NR
V-5
Greenland
29F
+GD
PI+
+minus
+minus
+NR
Diffusea
troph
y(M
RI)
V-9
Greenland
15F
+B
MR
TB
R+
NR
NR
+minus
NR
NR
NR
[19]
X4015
c2762CgtT(pGln858lowast
)Iran
14F
+Motor
defect
TB
RPI
NR
++
+minus
++
Diffusea
troph
y(M
RI)
X404
1Iran
10M
+B
TB
RPI
NR
++
+minus
++
Diffusea
troph
y(M
RI)
R104
2Iran
30M
+NR
TB
RPI
NR
NR
NR
NR
NR
NR
+NR
[24]
NAPO
6c2
629GgtA(G
ly877A
rg)
Italy
10Mminus
GD
BR
PI+
++
+minus
++
Diffusea
troph
y(M
RI)
[12]
Ac5
46Cgt
A(Phe182L
eu)
Japan
22Fminus
GD
TB
RPI
++
++
++
+Diffusea
troph
y(M
RI)
[14]
F37
c2236GgtA(A
la746Th
r)Ch
ina
53Fminus
NA
TB
Rminusminus
+minus
NR
++
Normal(M
RI)
EK1
China
50Mminus
NA
TB
RPIminusminus
+minus
NR
++
Normal(M
RI)
Y56
China
39Mminus
NA
TB
RPIminusminus
+minus
NR
++
Normal(M
RI)
[15]
H1288
c3274AgtG(pGly1014Ser)
China
48Fminus
NA
TB
RPI
NR
NR
NR
NR
NR
NR
+Normal(M
RI)
H496
c2236GgtA(A
la746Th
r)Ch
ina
49Mminus
NA
TB
RPI
NR
NR
NR
NR
NR
NR
+NR
H2120
c2236GgtA(A
la746Th
r)Ch
ina
51Fminus
NA
TB
RPI
NR
NR
NR
NR
NR
NR
+NR
[16]
NR
c3176CgtG(Leu1059Arg)
c3253delC(L1085wfsX1088)
China
17M
+A
BR
++
+NRminus
++
Normal(M
RI)
NR
China
17F
+AD
BR
++
+NRminus
++
Normal(M
RI)
Aanx
ietyA
Oage
ofon
setB
bradykinesiaB
SBa
binski
sign
CDcognitiv
edysfu
nctio
nDd
epression
DYS
dystoniaF
femaleFA
fatigueF
Hfam
ilyhisto
ryG
genderGDgaitd
isturbanceISinitia
lsymptom
Mm
aleMC
myoclo
nusMSmotor
symptom
NR
notreportedPIposturalinstabilityPT
posturaltremorR
rigidity
SUP
supranuclear
upgaze
palsy
Ttremor
BioMed Research International 5
ATP13A2 ProteaseX
CD63120572-Synuclein
Exosome
Degradation
LysosomeX XXXX
XXXXX
XXXX
MVBsAutophagosome
Intracellular
Externalisation
Extracellular
(a)
ATP13A2++ ATP13A2minusminus
ATP ATP
Degeneration
Mitochondria
ATPATP
Ca2+
ROS
(b)
Figure 1 Model of how ATP13A2 expression may affect lysosomes and mitochondria to prevent neurodegeneration (a) After 120572-synucleinhas been internalized by autophagosomes it can be immediately degraded in lysosomes containing ATP13A2 or secreted out of the cell viamultivesicular bodies (MVBs) also containing ATP13A2 Both routes prevent intracellular accumulation of 120572-synuclein (b) Knocking outATP13A2 expression in neurons leads to mitochondrial defects resulting in higher intracellular levels of reactive oxygen species (ROS) andCa2+ both of which contribute to neurodegeneration
ATP13A2 interacts preferentially with 120572-synuclein consistentwith a recent study showing that ATP13A2 colocalized with120572-synuclein in Lewy bodies but not with 120573-amyloid [38]
In addition to ensuring proper lysosomal functionATP13A2 may work in mitochondria such that the reducedactivity of ATP13A2 mutants may lead to mitochondrialdefects that contribute to neurodegeneration (Figure 1(b))[43] Fibroblasts from patients with KRS showed lowermitochondrial membrane potential and ATP synthesis ratesthan fibroblasts from healthy individuals [33] Cell culturesdeficient in ATP13A2 showed lower levels of autophagythan healthy cells leading to higher levels of reactiveoxygen species and concomitant oxidative stress [44]
Overexpressing ATP13A2 in neurons inhibited cadmium-induced mitochondrial fragmentation while silencingATP13A2 expression induced mitochondrial fragmentation[45] (Figure 1(b)) That same study further showed thatincreasing or decreasing ATP13A2 expression substantiallyshortened the neurites of primary midbrain DA neuronswithout affecting neurites of cortical neurons This maymean that the morphological and functional integrity of DAneurons depends on well-controlled ATP13A2 expression[45]
The available evidence suggests that ATP13A2 by sup-porting lysosomal andmitochondrial function helps preventthe 120572-synuclein aggregation associated with Parkinsonism
6 BioMed Research International
[46ndash49] The implication is that the ATP13A2 mutationslinked to KRS and other forms of PD are loss-of-functionmutations that reduce ATP13A2 activity sufficiently to induceneurodegeneration Future studies should examine in detailthe activity localization and binding partners of thesemutant proteins
42 ATP13A2 and Cation Accumulation ATP13A2 plays acritical role in the transmembrane transport of manganeseand zinc and perhaps of iron and cadmium as well [15]abnormal accumulation of any of these cations can causeneurodegeneration [41 50ndash52] Thus patients with PD havebeen reported to show elevated levels of manganese and zincin serum and cerebrospinal fluid [53ndash55] andmanganese andzinc exposure are significant environmental risk factors forPD [56 57] ATP13A2 helps protect cells from this toxicity byregulating the homeostasis ofmanganese and zinc in neurons[41 44 58 59] It may be that dysregulation of ATP13A2expression disrupts the homeostasis of manganese and zincin the brain leading to neurodegeneration
This possibility is consistent with the interpretation of theabnormal hypointensity in the putamina and caudate nucleiof patients with KRS in T2lowast diffuse MRI images as irondeposits (see Section 3) This finding led those authors topropose KRS with iron deposits as a distinct condition calledneurodegeneration with brain iron accumulation (NBIA)[20] Indeed iron accumulation was reported in the substan-tia nigra of PD patients [60] where it was particularly abun-dant in DA neurons [61] Administering the iron chelatordeferiprone to an animal model of PD induced by oxidativestress improved motor function and increased dopaminelevels in the striatum [62] In a pilot randomized clinical trialdouble-blind and placebo-controlled deferiprone showedsome ability to delay or reverse the progression of PD [62]
How mutations in ATP13A2may affect cation depositionis unclear We speculate that loss-of-function mutations inATP13A2 may work similarly to silencing of the PANK2gene which disrupts normal cation transfer and leads tomitochondrial and lysosomal dysfunction and ultimatelyto cation accumulation in the brain [63 64] In this wayATP13A2mutants may trigger deposition of the cations zincmanganese and iron leading to metal-induced oxidativedamage and ultimately causing decreases in glutathione per-oxidase activity glutathione (GSH) levels andmitochondrialComplex I activity as well as increases in levels of basal lipidperoxidation free radicals and glutamate [65ndash67] The netresult is significant neuronal loss that is the distinguishingpathological feature of PD
This proposed mechanism implies that regulating orrestoring the homeostasis of neurotoxic cations may be aneuroprotective therapy for patients with PD However onlytwo of the 37 PD patients with ATP13A2 mutations that wereviewed showed cation accumulation on T2lowast diffuse MRIimages (Table 2) and direct postmortem pathological evi-dence for metal accumulation in PD is lacking [20 33] Fur-ther studies are urgently needed to clarify whether ATP13A2mutations contribute to PD by increasing susceptibility tocation toxicity
5 ATP13A2 Mutations A Link betweenParkinsonism and NCLs
ATP13A2mutations have been identified not only in patientswith Parkinsonism but also in patients with neuronal ceroidlipofuscinoses (NCLs) [10] NCLs are a group of neurode-generative disorders that are also lysosomal storage diseasesClinical manifestations are seizures progressive cognitiveand motor decline and failing vision The pathologicalhallmark of NCLs is accumulation of autofluorescent lipopig-ment within neuronal lysosomes [68]
Recently the mutation c2429CgtG in exon 22 ofATP13A2 predicted to result in the amino acid substitutionpMet810Arg was identified in a Belgian family withNCLs [10] Affected individuals showed not only typicalNCL symptoms but also extrapyramidal involvementPostmortem pathological examination revealed extensivelipofuscin deposits in the cortex basal nuclei cerebellumand retinamdashbut not the white mattermdashand electronmicroscopy showed whorled lamellar inclusions typical ofNCLs [10] A link between ATP13A2 mutations and NCLpathogenesis is further supported by studies in animalmodels [69 70] In fact mice deficient in ATP13A2 exhibitedneuronal ceroid lipofuscinosis 120572-synuclein accumulationand age-dependent sensorimotor deficits suggesting that PDand NCLs share a pathogenic mechanism [71]
A shared disease pathwaymay help explain earlier reportsof individuals who demonstrate an ldquooverlappingrdquo neurode-generative syndrome combining Parkinsonism and NCLs[72ndash76] ATP13A2 is a lysosomal transport protein that helpsmaintain optimal pH in lysosomes [46] and ceramide ismetabolized in lysosomes [77] The apoptosis that appears tocause NCLs is associated with increased levels of ceramide[78 79] which have also been linked to 120572-synuclein deposi-tion whichmay contribute to PDpathogenesis [80] Itmay bethat ATP13A2 helps regulate ceramide metabolism such thatsignificant changes in ATP13A2 activitymay contribute to thepathogenesis of both PD and NCLs This model is similar tothat of the lysosomal storage disorder called Gaucher diseaseThe homozygousmutations in the 120573-glucocerebrosidase genethat cause Gaucher disease also increase risk of PD [81]Both diseases arise because lysosomal dysfunction leadsto excessive aggregation of substrates that normally aredegraded Analogously lysosomal dysfunction may underliethe clinically different neurodegenerative disorders of PD andNCLs
6 Summary
Much has been learned about the physiological functionsof ATP13A2 since mutations in the ATP13A2 gene werefirst linked to autosomal recessive familial KRS [7] Patientswith such mutations show onset at earlier ages than patientswith other forms of PD as well as some atypical clinicalsymptoms such as pyramidal degeneration supranuclearpalsy cognitive impairment and dystonia Studies in animalmodels of PD and in cultures of cells taken from patients withKRS and other types of PD suggest that ATP13A2 is important
BioMed Research International 7
for proper functioning of lysosomes and mitochondria andperhaps for clearance of divalent metals defects in any ofthese three processes are tightly associated with neurodegen-eration Nevertheless more studies are needed that directlyexamine how PD-associated mutations in ATP13A2 affectthe activity and localization of the protein and ultimatelythe integrity of these three processes ATP13A2 mutationsthat affect one of these processes lysosomal functioningmay simultaneously increase the risk of PD and NCLs Inotherwords these quite clinically different diseasesmay sharea mechanism of lysosomal dysfunction If further studiesvalidate the literature the ATP13A2 gene andor protein maybecome a suitable therapeutic target for treating both PD andNCLs
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Work by the authors related to this review was supportedby the Sichuan Key Project of Science and Technology (no2010SZ0086) and the National Natural Science Foundationof China (no 30700243)
References
[1] S Lesage and A Brice ldquoParkinsonrsquos disease from monogenicforms to genetic susceptibility factorsrdquo Human MolecularGenetics vol 18 no R1 pp R48ndashR59 2009
[2] V Bonifati ldquoGenetics of Parkinsonrsquos diseasemdashstate of the artrdquoParkinsonism amp Related Disorders vol 20 supplement 1 ppS23ndashS28 2014
[3] F Coppede ldquoGenetics and epigenetics of Parkinsonrsquos diseaserdquoScientific World Journal vol 2012 Article ID 489830 12 pages2012
[4] S Lesage E Lohmann F Tison F Durif A Durr and ABrice ldquoGene symbol PARK2 Disease parkinsonism juvenileautosomal recessiverdquoHuman genetics vol 123 no 1 article 1142008
[5] V Bonifati P Rizzu M J Van Baren et al ldquoMutations inthe DJ-1 gene associated with autosomal recessive early-onsetparkinsonismrdquo Science vol 299 no 5604 pp 256ndash259 2003
[6] Y Li H Tomiyama K Sato et al ldquoClinicogenetic study ofPINK1mutations in autosomal recessive early-onset parkinson-ismrdquo Neurology vol 64 no 11 pp 1955ndash1957 2005
[7] A Ramirez A Heimbach J Grundemann et al ldquoHeredi-tary parkinsonism with dementia is caused by mutations inATP13A2 encoding a lysosomal type 5 P-type ATPaserdquo NatureGenetics vol 38 no 10 pp 1184ndash1191 2006
[8] H Tomiyama H Yoshino K Ogaki et al ldquoPLA2G6 variant inParkinsons diseaserdquo Journal of Human Genetics vol 56 no 5pp 401ndash403 2011
[9] A Di Fonzo M C J Dekker P Montagna et al ldquoFBXO7mutations cause autosomal recessive early-onset parkinsonian-pyramidal syndromerdquo Neurology vol 72 no 3 pp 240ndash2452009
[10] J Bras A Verloes S A Schneider S E Mole and R J Guer-reiro ldquoMutation of the parkinsonism gene ATP13A2 causesneuronal ceroid-lipofuscinosisrdquo Human Molecular Geneticsvol 21 no 12 pp 2646ndash2650 2012
[11] A Di Fonzo H F Chien M Socal et al ldquoATP13A2 missensemutations in juvenile Parkinsonism and young onset Parkinsondiseaserdquo Neurology vol 68 no 19 pp 1557ndash1562 2007
[12] Y P Ning K Kanai H Tomiyama et al ldquoPARK9-linkedparkinsonism in eastern Asia mutation detection in ATP13A2and clinical phenotyperdquo Neurology vol 70 no 16 part 2 pp1491ndash1493 2008
[13] M Funayama H Tomiyama R M Wu et al ldquoRapid screeningof ATP13A2 variant with highresolution melting analysisrdquoMovement Disorders vol 25 no 14 pp 2434ndash2437 2010
[14] C H Lin E K Tan M L Chen et al ldquoNovel ATP13A2 variantassociated with Parkinson disease in Taiwan and SingaporerdquoNeurology vol 71 no 21 pp 1727ndash1732 2008
[15] C-M Chen C-H Lin H-F Juan et al ldquoATP13A2 variabilityin Taiwanese Parkinsonrsquos diseaserdquo American Journal of MedicalGenetics B Neuropsychiatric Genetics vol 156 no 6 pp 720ndash729 2011
[16] J Park PMehta A A Cooper et al ldquoPathogenic effects of novelmutations in the P-type ATPase ATP13A2 (PARK9) causingKufor-Rakeb syndrome a form of early-onset parkinsonismrdquoHuman Mutation vol 32 no 8 pp 956ndash964 2011
[17] L H Zhu X G Luo Y S Zhou et al ldquoLack of associationbetween three single nucleotide polymorphisms in the PARK9PARK15 and BST1 genes and Parkinsonrsquos disease in the north-ern Han Chinese populationrdquo Chinese Medical Journal vol 125no 4 pp 588ndash592 2012
[18] A Djarmati J Hagenah K Reetz et al ldquoATP13A2 variants inearly-onset Parkinsonrsquos disease patients and controlsrdquo Move-ment Disorders vol 24 no 14 pp 2104ndash2111 2009
[19] M Malakouti-Nejad G A Shahidi M Rohani et al ldquoIdenti-fication of pGln858lowast in ATP13A2 in two EOPD patients andpresentation of their clinical featuresrdquoNeuroscience Letters vol577 pp 106ndash111 2014
[20] S A Schneider C Paisan-Ruiz N P Quinn et al ldquoATP13A2mutations (PARK9) cause neurodegeneration with brain ironaccumulationrdquoMovement Disorders vol 25 no 8 pp 979ndash9842010
[21] C Y Fong A Rolfs T Schwarzbraun C Klein and F J KOrsquoCallaghan ldquoJuvenile parkinsonism associated with heterozy-gous frameshift ATP13A2 gene mutationrdquo European Journal ofPaediatric Neurology vol 15 no 3 pp 271ndash275 2011
[22] D Crosiers B Ceulemans B Meeus et al ldquoJuvenile dystonia-parkinsonism and dementia caused by a novel ATP13A2frameshift mutationrdquo Parkinsonism and Related Disorders vol17 no 2 pp 135ndash138 2011
[23] H Eiberg L Hansen L Korbo et al ldquoNovel mutation inATP13A2 widens the spectrum of Kufor-Rakeb syndrome(PARK9)rdquo Clinical Genetics vol 82 no 3 pp 256ndash263 2012
[24] L Santoro G J Breedveld F Manganelli et al ldquoNovelATP13A2(PARK9) homozygous mutation in a family with markedphenotype variabilityrdquo Neurogenetics vol 12 no 1 pp 33ndash392011
[25] Q Z Fei L Cao Q Xiao et al ldquoLack of association betweenATP13A2 Ala746Thr variant and Parkinsons disease in Hanpopulation of mainland Chinardquo Neuroscience Letters vol 475no 2 pp 61ndash63 2010
8 BioMed Research International
[26] X Y Mao J M Burgunder Z J Zhang et al ldquoATP13A2G2236A variant is rare in patients with early-onset Parkinsonrsquosdisease and familial Parkinsonrsquos disease from mainland ChinardquoParkinsonism and Related Disorders vol 16 no 3 pp 235ndash2362010
[27] A Y Y Chan L Baum N L S Tang et al ldquoThe role ofthe Ala746Thr variant in the ATP13A2 gene among Chinesepatients with Parkinsonrsquos diseaserdquo Journal of Clinical Neuro-science vol 20 no 5 pp 761ndash762 2013
[28] H Darvish A Movafagh M D Omrani et al ldquoDetectionof copy number changes in genes associated with Parkinsonrsquosdisease in Iranian patientsrdquo Neuroscience Letters vol 551 pp75ndash78 2013
[29] C Vilarino-Guell A I Soto S J Lincoln et al ldquoATP13A2variability in Parkinson diseaserdquo Human Mutation vol 30 no3 pp 406ndash410 2009
[30] A Rakovic B Stiller A Djarmati et al ldquoGenetic associationstudy of the P-type ATPase ATP13A2 in late-onset ParkinsonrsquosdiseaserdquoMovement Disorders vol 24 no 3 pp 429ndash433 2009
[31] A S Najim Al-Din A Wriekat A Mubaidin M Dasoukiand M Hiari ldquoPallido-pyramidal degeneration supranuclearupgaze paresis and dementia Kufor-Rakeb syndromerdquo ActaNeurologica Scandinavica vol 89 no 5 pp 347ndash352 1994
[32] D R Williams A Hadeed A S Najim al-Din A Wreikatand A J Lees ldquoKufor Rakeb disease autosomal recessivelevodopa-responsive Parkinsonism with pyramidal degenera-tion supranuclear gaze palsy and dementiardquoMovement Disor-ders vol 20 no 10 pp 1264ndash1271 2005
[33] M I Behrens N Bruggemann P Chana et al ldquoClinicalspectrum of Kufor-Rakeb syndrome in the Chilean kindredwith ATP13A2 mutationsrdquoMovement Disorders vol 25 no 12pp 1929ndash1937 2010
[34] P J Schultheis T T Hagen K K OrsquoToole et al ldquoCharacteriza-tion of the P5 subfamily of P-type transport ATPases in micerdquoBiochemical and Biophysical Research Communications vol 323no 3 pp 731ndash738 2004
[35] B Schroder CWrocklage C Pan et al ldquoIntegral and associatedlysosomal membrane proteinsrdquo Traffic vol 8 no 12 pp 1676ndash1686 2007
[36] H Matsui F Sato S Sato et al ldquoATP13A2 deficiency inducesa decrease in cathepsin D activity fingerprint-like inclusionbody formation and selective degeneration of dopaminergicneuronsrdquo FEBS Letters vol 587 no 9 pp 1316ndash1325 2013
[37] B Dehay A Ramirez M Martinez-Vicente et al ldquoLoss of P-type ATPase ATP13A2PARK9 function induces general lyso-somal deficiency and leads to Parkinson disease neurodegen-erationrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 109 no 24 pp 9611ndash9616 2012
[38] K E Murphy L Cottle A M Gysbers A A Cooper and GM Halliday ldquoATP13A2 (PARK9) protein levels are reduced inbrain tissue of cases with Lewy bodiesrdquo Acta NeuropathologicaCommunications vol 1 article 11 2013
[39] G K Tofaris ldquoLysosome-dependent pathways as a unifyingtheme in Parkinsonrsquos diseaserdquo Movement Disorders vol 27 no11 pp 1364ndash1369 2012
[40] S M Kong B K Chan J S Park et al ldquoParkinsonrsquos disease-linked human PARK9 ATP13A2 maintains zinc homeosta-sis and promotes 120572-Synuclein externalization via exosomesrdquoHuman Molecular Genetics vol 23 no 11 pp 2816ndash2833 2014
[41] A D Gitler A Chesi M L Geddie et al ldquo120572-Synuclein ispart of a diverse and highly conserved interaction network that
includes PARK9 and manganese toxicityrdquo Nature Genetics vol41 no 3 pp 308ndash315 2009
[42] M Usenovic E Tresse J R Mazzulli J P Taylor and DKrainc ldquoDeficiency ofATP13A2 leads to lysosomal dysfunction120572-synuclein accumulation and neurotoxicityrdquo The Journal ofNeuroscience vol 32 no 12 pp 4240ndash4246 2012
[43] J S Park B Koentjoro D Veivers A Mackay-Sim and C MSue ldquoParkinsonrsquos disease-associated human ATP13A2 (PARK9)deficiency causes zinc dyshomeostasis andmitochondrial dys-functionrdquo Human Molecular Genetics vol 23 no 11 pp 2802ndash2815 2014
[44] A M Gusdon J Zhu B van Houten and C T ChuldquoATP13A2 regulates mitochondrial bioenergetics throughmacroautophagyrdquo Neurobiology of Disease vol 45 no 3 pp962ndash972 2012
[45] D Ramonet A Podhajska K Stafa et al ldquoPARK9-associatedATP13A2 localizes to intracellular acidic vesicles and regulatescation homeostasis and neuronal integrityrdquo Human MolecularGenetics vol 21 no 8 pp 1725ndash1743 2012
[46] R A Nixon D S Yang and J H Lee ldquoNeurodegenerativelysosomal disorders a continuum from development to lateagerdquo Autophagy vol 4 no 5 pp 590ndash599 2008
[47] B Dehay M Martinez-Vicente G A Caldwell et al ldquoLysoso-mal impairment in Parkinsonrsquos diseaserdquo Movement Disordersvol 28 no 6 pp 725ndash732 2013
[48] C W Olanow and P Brundin ldquoParkinsonrsquos disease and alphasynuclein is Parkinsonrsquos disease a prion-like disorderrdquo Move-ment Disorders vol 28 no 1 pp 31ndash40 2013
[49] J Bove M Martınez-Vicente and M Vila ldquoFighting neu-rodegeneration with rapamycin mechanistic insightsrdquo NatureReviews Neuroscience vol 12 no 8 pp 437ndash452 2011
[50] K Schmidt D M Wolfe B Stiller and D A Pearce ldquoCd2+Mn2+ Ni2+ and Se2+ toxicity to Saccharomyces cerevisiaelacking YPK9p the orthologue of human ATP13A2rdquo Biochem-ical and Biophysical Research Communications vol 383 no 2pp 198ndash202 2009
[51] P G Mastroberardino E K Hoffman M P Horowitz et al ldquoAnovel transferrinTfR2-mediated mitochondrial iron transportsystem is disrupted in Parkinsonrsquos diseaserdquo Neurobiology ofDisease vol 34 no 3 pp 417ndash431 2009
[52] C T Sheline J Zhu W Zhang C Shi and A Cai ldquoMitochon-drial inhibitor models of Huntingtonrsquos disease and Parkinsonrsquosdisease induce zinc accumulation and are attenuated by inhibi-tion of zinc neurotoxicity in vitro or in vivordquoNeurodegenerativeDiseases vol 11 no 1 pp 49ndash58 2013
[53] T Fukushima X Tan Y Luo and H Kanda ldquoSerum vitaminsand heavy metals in blood and urine and the correlationsamong them in parkinsonrsquos disease patients inChinardquoNeuroepi-demiology vol 36 no 4 pp 240ndash244 2011
[54] I Hozumi T Hasegawa A Honda et al ldquoPatterns of levelsof biological metals in CSF differ among neurodegenerativediseasesrdquo Journal of the Neurological Sciences vol 303 no 1-2pp 95ndash99 2011
[55] F J Jimenez-Jimenez P Fernandez-Calle M Martınez-Vanaclocha et al ldquoSerum levels of zinc and copper in patientswith Parkinsonrsquos diseaserdquo Journal of the Neurological Sciencesvol 112 no 1-2 pp 30ndash33 1992
[56] T R Guilarte ldquoManganese and Parkinsonrsquos disease a criticalreview and new findingsrdquo Environmental Health Perspectivesvol 118 no 8 pp 1071ndash1080 2010
BioMed Research International 9
[57] P Pals B van Everbroeck B Grubben et al ldquoCase-controlstudy of environmental risk factors for Parkinsonrsquos disease inBelgiumrdquo European Journal of Epidemiology vol 18 no 12 pp1133ndash1142 2003
[58] G Rentschler L Covolo A Ahmadi Haddad R G LucchiniS Zoni and K Broberg ldquoATP13A2 (PARK9) polymorphismsinfluence the neurotoxic effects of manganeserdquo NeuroToxicol-ogy vol 33 no 4 pp 697ndash702 2012
[59] J Tan T Zhang L Jiang et al ldquoRegulation of intracellularmanganese homeostasis by Kufor-Rakeb syndrome-associatedATP13A2 proteinrdquo Journal of Biological Chemistry vol 286 no34 pp 29654ndash29662 2011
[60] D Berg andHHochstrasser ldquoIronmetabolism in parkinsoniansyndromesrdquo Movement Disorders vol 21 no 9 pp 1299ndash13102006
[61] A E Oakley J F Collingwood J Dobson et al ldquoIndividualdopaminergic neurons show raised iron levels in Parkinsondiseaserdquo Neurology vol 68 no 21 pp 1820ndash1825 2007
[62] D Devos C Moreau and J C Devedjian ldquoTargeting chelatableiron as a therapeutic modality in Parkinsonrsquos diseaserdquo Antioxi-dants and Redox Signaling vol 21 no 2 pp 195ndash210 2014
[63] M Poli M Derosas S Luscieti et al ldquoPantothenate kinase-2 (Pank2) silencing causes cell growth reduction cell-specificferroportin upregulation and iron deregulationrdquo Neurobiologyof Disease vol 39 no 2 pp 204ndash210 2010
[64] T Tsunemi and D Krainc ldquoZn2+ dyshomeostasis caused by lossof ATP13A2PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulationrdquo Human Molecular Genetics vol 23no 11 pp 2791ndash2801 2014
[65] J Xu E Marzetti A Y Seo J Kim T A Prolla and CLeeuwenburgh ldquoThe emerging role of iron dyshomeostasis inthe mitochondrial decay of agingrdquo Mechanisms of Ageing andDevelopment vol 131 no 7-8 pp 487ndash493 2010
[66] M B H Youdim and P Riederer ldquoThe role of iron in senescenceof dopaminergic neurons in Parkinsonrsquos diseaserdquo Journal ofNeural Transmission Supplement no 40 pp 57ndash67 1993
[67] P Karki E Lee and M Aschner ldquoManganese neurotoxicity afocus on glutamate transportersrdquo Annals of Occupational andEnvironmental Medicine vol 25 no 1 article 4 2013
[68] H H Goebel L Gerhard E Kominami and M Hal-tia ldquoNeuronal ceroid-lipofuscinosismdashlate-infantile or Jansky-Bielschowsky typemdashrevisitedrdquo Brain Pathology vol 6 no 3 pp225ndash228 1996
[69] A Wohlke U Philipp P Bock et al ldquoA one base pair deletionin the canine ATP13A2 gene causes exon skipping and late-onset neuronal ceroid lipofuscinosis in the Tibetan terrierrdquoPLoS Genetics vol 7 no 10 Article ID e1002304 2011
[70] F H G Farias R Zeng G S Johnson et al ldquoA truncatingmuta-tion in ATP13A2 is responsible for adult-onset neuronal ceroidlipofuscinosis in Tibetan terriersrdquo Neurobiology of Disease vol42 no 3 pp 468ndash474 2011
[71] P J Schultheis S M Fleming A K Clippinger et al ldquoAtp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis limited120572-synuclein accumulation and age-dependent sensorimotordeficitsrdquo Human Molecular Genetics vol 22 no 10 pp 2067ndash2082 2013
[72] J G Burneo T Arnold C A Palmer R I Kuzniecky SJ Oh and E Faught ldquoAdult-onset neuronal ceroid lipofusci-nosis (Kufs disease) with autosomal dominant inheritance inAlabamardquo Epilepsia vol 44 no 6 pp 841ndash846 2003
[73] S F Berkovic S Carpenter F Andermann E Andermann andL S Wolfe ldquoKufsrsquo disease a critical reappraisalrdquo Brain vol 111no 1 part 1 pp 27ndash62 1988
[74] P C G Nijssen E Brusse A C M Leyten J J Martin JL J M Teepen and R A C Roos ldquoAutosomal dominantadult neuronal ceroid lipofuscinosis parkinsonism due to bothstriatal and nigral dysfunctionrdquoMovement Disorders vol 17 no3 pp 482ndash487 2002
[75] P E M Taschner N de Vos A D Thompson et al ldquoChro-mosome 16 microdeletion in a patient with juvenile neuronalceroid lipofuscinosis (Batten disease)rdquoThe American Journal ofHuman Genetics vol 56 no 3 pp 663ndash668 1995
[76] A Y Lavrov E S Ilyna E Y Zakharova A M Boukina andS V Tishkanina ldquoThe first three Russian cases of classical late-infantile neuronal ceroid lipofuscinosisrdquo European Journal ofPaediatric Neurology vol 6 no 3 pp 161ndash164 2002
[77] J Bras A Singleton M R Cookson and J Hardy ldquoEmerg-ing pathways in genetic Parkinsonrsquos disease potential role ofceramide metabolism in Lewy body diseaserdquo FEBS Journal vol275 no 23 pp 5767ndash5773 2008
[78] S El Haddad M Khoury M Daoud et al ldquoCLN5 and CLN8protein association with ceramide synthase biochemical andproteomic approachesrdquoElectrophoresis vol 33 no 24 pp 3798ndash3809 2012
[79] D Persaud-Sawin T Mousallem C Wang A Zucker E Kom-inami and R N Boustany ldquoNeuronal ceroid lipofuscinosis acommon pathwayrdquo Pediatric Research vol 61 no 2 pp 146ndash152 2007
[80] T J van Ham K L Thijssen R Breitling R M W Hofstra RH A Plasterk and E A A Nollen ldquoC elegansmodel identifiesgenetic modifiers of 120572-synuclein inclusion formation duringagingrdquo PLoS Genetics vol 4 no 3 Article ID e1000027 2008
[81] A Halperin D Elstein and A Zimran ldquoIncreased incidenceof Parkinson disease among relatives of patients with Gaucherdiseaserdquo Blood Cells Molecules and Diseases vol 36 no 3 pp426ndash428 2006
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
International Journal of
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neuroscience Journal
Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Psychiatry Journal
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Brain ScienceInternational Journal of
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neurodegenerative Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International 3
Table 1 Review of the literature on ATP13A2mutations associated with Parkinsonrsquos disease
Ref Author Year Country of patient origin Mutation Notes
[7] Ramirez et al 2006 Chile Jordanc3057delC (p1019GfsX1021)c1306+5GgtA (pG399 L435del)c1632 1653dup22 (pLeu552fsX788)
[11] Di Fonzo et al 2007 Brazil Italyc1510GgtC (pGly504Arg)c35CgtT (pThr12Met)c1597GgtA (pGly533Arg)
[12] Ning et al 2008 Japan c546CgtA (pPhe182Leu)[14] Lin et al 2008 Taiwan Singapore c2236GgtA (pAla746Thr) Ethnic Chinese
[18] Djarmati et al 2009 Various European countriesc746CgtT (pAla249Val)c844AgtT (pSer282Cys)c2939GgtA (pArg980His)
Iran c1346GgtA (pArg449Gln)[20] Schneider et al 2010 Pakistan c1103 1104insGA (pThr367fsX29)[25] Fei et al 2010 China (mainland) c2236GgtA (pAla746Thr)[26] Mao et al 2010 China (mainland) c2236GgtA (pAla746Thr)[13] Funayama et al 2010 Japan c2236GgtA (pAla746Thr)[15] Chen et al 2011 Taiwan c3274AgtG (pGly1014Ser) Ethnic Chinese[21] Fong et al 2011 Lithuania c1108 1120del13 (pArg370fsX390)
[16] Park et al 2011 Various Asian countries c3176TgtG (pLeu1059Arg)c3253delC (pL1085wfsX1088)
[22] Crosiers et al 2011 Afghanistan c2742 2743delTT (pF851CfsX856)[23] Eiberg et al 2012 Greenland c2473CgtAA (pLeu825fs) Ethnic Inuits[17] Zhu et al 2012 China (mainland) c1754GgtT (p Ala585Asp) Ethnic Chinese[24] Santoro et al 2011 Italy c2629GgtA (pGly877Arg)[27] Chan et al 2013 China (Hong Kong) c2236GgtA (pAla746Thr) Ethnic Chinese[28] Darvish et al 2013 Iran Deletion of exon 2[19] Malakouti-Nejad et al 2014 Iran c2762CgtT (pGln858lowast)
4 Physiological Role of ATP13A2 andLink to PD
41 ATP13A2 and Function of Lysosomes and Mitochon-dria ATP13A2 encodes a lysosomal transmembrane proteinbelonging to the 5P-type ATPase subfamily [34] Wild-typeATP13A2 localizes to the lysosome while all mutant formsassociated with PD localize to the endoplasmic reticulum(ER) [9 16 35 36] In contrast to genes for other 5P-type ATPases ATP13A2 in mice is expressed mainly in thebrain suggesting a brain-specific function ATP13A2 levelsin the substantia nigra are substantially lower in postmortemtissue biopsies of patients with sporadic PD than in thecorresponding samples from healthy controls [37 38] butthey are higher in survival dopaminergic (DA) neuronsof patients than in those of controls [37] ATP13A2 levelsare particularly high in the cytosol of nigral dopaminergicneurons where the protein accumulates in Lewy bodies [37]
These circumstantial data implicate ATP13A2 in thepathogenesis andor progression of PD but more directevidence requires insights into the function of the ATP13A2protein Studies with cultures of fibroblast cells and DA cellstaken from PD patients with ATP13A2 mutations showed
that inhibiting ATP13A2 function decreased the ability oflysosomes to degrade proteins and mediate clearance ofautophagosomes [37] These cellular functions returned tonear-normal levels afterATP13A2 activity was restoredTheseresults suggest that ATP13A2 is required for normal lysosomefunctionwhich is in turn required for preventing120572-synucleinaggregation in neurons (Figure 1(a)) This aggregation is apathological hallmark of both sporadic and familial PD [39]
Several additional studies provide further evidencethat ATP13A2 prevents 120572-synuclein aggregation SH-SY5Y cultures overexpressing ATP13A2 showed lowerintracellular levels of 120572-synuclein perhaps because ofincreased 120572-synuclein export via multivesicular bodies(MVBs) (Figure 1(a)) [40] In both whole-animal andneuronal culture models of PD coexpressing ATP13A2 with120572-synuclein led to lower synuclein levels in DA neurons thanexpressing synuclein alone [41] Neuronal cultures lackingthe ATP13A2 gene showed significantly higher endogenouslevels of 120572-synuclein than did the corresponding wild-typeneurons [42] Intriguingly the ATP13A2-knockout neuronsdid not show elevated levels or aggregates of tau proteinwhich may play an important role in the pathogenesis ofAlzheimerrsquos disease (AD) This raises the possibility that
4 BioMed Research International
Table2Clinicalfeatures
ofpatie
ntsw
ithParkinsonrsquos
diseasea
ndmutations
intheA
TP13A2
gene
Ref
Internalcode
Mutation
Cou
ntry
oforigin
AO(years)
GFH
ISMS
MC
SUP
DYS
CDH
BSRe
spon
seto
levodo
paIm
agingfin
ding
s
[26]
V44
1632
1653du
p22(552LeufsX
788)
Jordan
12M
+B
MR
RB
RPI
++minus
++
++
Diffusea
troph
y(M
RI)
V48
Jordan
15M
+B
RB
RPI
++
++
++
+Diffusea
troph
y(M
RI)
V49
Jordan
13M
+MR
RB
RPI
+minus
++
++
+Diffusea
troph
y(M
RI)
V53
Jordan
12F
+B
BR
PI+minus
++
++
+NR
[1]
II-8
c3057delC(p10
19GfsX1021)
c1306+
5GgtA(pG399L4
35del)
Chile
18M
+BR
FTB
R+
+NR
++
+Never
tried
Enlarged
sulci(CT
)
II-9
Chile
17M
+BR
BR
TB
RPI
+minus
NR
++minus
minusMild
diffusea
troph
ycaud
ate
hypo
intensity
(MRI)
II-10
Chile
15F
+B
FBR
TB
RPI
++
NR
+minus
+minus
NR
II-11
Chile
12M
+FBR
TB
RPI
++
NR
++
+minus
Diffusea
troph
y(C
T)
[11]
BR-304
2c1510GgtC(G
ly504A
rg)
Brazil
12Mminus
BB
RPI
++
NR
++
++
Diffusea
troph
y(C
T)VE2
9c3
5CgtT(Th
r12M
et)
Italy
30M
+NA
TB
RPI
NR
++minusminus
++
NR
PK-69-1
c1597CgtA(G
ly533A
rg)
Italy
40M
+NA
BR
PINR
++minus
++
+NR
[18]
L-1349
c746
CgtT(A
la249V
al)
Germany
31Fminus
TTB
RPI
NR
+minus
NR
+minus
+Normal(M
RI)
L-1928
c844
AgtT(Ser282C
ys)
Norway
20Mminus
PIR
PINR
+minus
NRminus
++
Normal(M
RI)
L-324
c1346GgtA(A
rg44
9Gln)
Iran
36Mminus
TB
RPI
NR
+minus
NR
++
+Cerebralatro
phy(C
T)P-55
c2939GgtA(A
rg980H
is)Serbia
35Fminus
PTTB
RPI
NR
+minus
NR
++
+Normal
[20]
NR
c11031104
insG
A(pTh
r367fsX2
9)Pakista
n16
Mminus
BMR
BR
PIminus
++
++
++
Diffusea
troph
y(M
RI)
[22]
II-3
c27422743delTT(pF851C
fsX8
56)
Afghanista
n10
Mminus
BMR
BR
PI+
++
+minus
++
Diffusea
troph
ybilateralhypo
intensity
inpu
taminaa
ndcaud
aten
uclei(MRI)
[21]
NR
c11081120del13
(pArg370fsX
390)
Lithuania
6Mminus
Dysarthria
DYS
TB
RPI
NRminus
+minus
NRminus
+Normal(M
RI)
[23]
VI-1
c2473CgtAA(pLeu825AsnfsX3
2)
Greenland
27F
+FA
NR
NR
NR
NR
++
+NR
Diffusea
troph
y(M
RI)
VI-6
Greenland
24M
+Weakn
ess
NR
NR
NR
++
++
NR
Diffusea
troph
y(M
RI)
V-1
Greenland
12M
+T
BR
++
++
++
NR
Normal(M
RI)
V-3
Greenland
10F
+CD
TB
Rminusminusminusminus
+minus
NR
NR
V-5
Greenland
29F
+GD
PI+
+minus
+minus
+NR
Diffusea
troph
y(M
RI)
V-9
Greenland
15F
+B
MR
TB
R+
NR
NR
+minus
NR
NR
NR
[19]
X4015
c2762CgtT(pGln858lowast
)Iran
14F
+Motor
defect
TB
RPI
NR
++
+minus
++
Diffusea
troph
y(M
RI)
X404
1Iran
10M
+B
TB
RPI
NR
++
+minus
++
Diffusea
troph
y(M
RI)
R104
2Iran
30M
+NR
TB
RPI
NR
NR
NR
NR
NR
NR
+NR
[24]
NAPO
6c2
629GgtA(G
ly877A
rg)
Italy
10Mminus
GD
BR
PI+
++
+minus
++
Diffusea
troph
y(M
RI)
[12]
Ac5
46Cgt
A(Phe182L
eu)
Japan
22Fminus
GD
TB
RPI
++
++
++
+Diffusea
troph
y(M
RI)
[14]
F37
c2236GgtA(A
la746Th
r)Ch
ina
53Fminus
NA
TB
Rminusminus
+minus
NR
++
Normal(M
RI)
EK1
China
50Mminus
NA
TB
RPIminusminus
+minus
NR
++
Normal(M
RI)
Y56
China
39Mminus
NA
TB
RPIminusminus
+minus
NR
++
Normal(M
RI)
[15]
H1288
c3274AgtG(pGly1014Ser)
China
48Fminus
NA
TB
RPI
NR
NR
NR
NR
NR
NR
+Normal(M
RI)
H496
c2236GgtA(A
la746Th
r)Ch
ina
49Mminus
NA
TB
RPI
NR
NR
NR
NR
NR
NR
+NR
H2120
c2236GgtA(A
la746Th
r)Ch
ina
51Fminus
NA
TB
RPI
NR
NR
NR
NR
NR
NR
+NR
[16]
NR
c3176CgtG(Leu1059Arg)
c3253delC(L1085wfsX1088)
China
17M
+A
BR
++
+NRminus
++
Normal(M
RI)
NR
China
17F
+AD
BR
++
+NRminus
++
Normal(M
RI)
Aanx
ietyA
Oage
ofon
setB
bradykinesiaB
SBa
binski
sign
CDcognitiv
edysfu
nctio
nDd
epression
DYS
dystoniaF
femaleFA
fatigueF
Hfam
ilyhisto
ryG
genderGDgaitd
isturbanceISinitia
lsymptom
Mm
aleMC
myoclo
nusMSmotor
symptom
NR
notreportedPIposturalinstabilityPT
posturaltremorR
rigidity
SUP
supranuclear
upgaze
palsy
Ttremor
BioMed Research International 5
ATP13A2 ProteaseX
CD63120572-Synuclein
Exosome
Degradation
LysosomeX XXXX
XXXXX
XXXX
MVBsAutophagosome
Intracellular
Externalisation
Extracellular
(a)
ATP13A2++ ATP13A2minusminus
ATP ATP
Degeneration
Mitochondria
ATPATP
Ca2+
ROS
(b)
Figure 1 Model of how ATP13A2 expression may affect lysosomes and mitochondria to prevent neurodegeneration (a) After 120572-synucleinhas been internalized by autophagosomes it can be immediately degraded in lysosomes containing ATP13A2 or secreted out of the cell viamultivesicular bodies (MVBs) also containing ATP13A2 Both routes prevent intracellular accumulation of 120572-synuclein (b) Knocking outATP13A2 expression in neurons leads to mitochondrial defects resulting in higher intracellular levels of reactive oxygen species (ROS) andCa2+ both of which contribute to neurodegeneration
ATP13A2 interacts preferentially with 120572-synuclein consistentwith a recent study showing that ATP13A2 colocalized with120572-synuclein in Lewy bodies but not with 120573-amyloid [38]
In addition to ensuring proper lysosomal functionATP13A2 may work in mitochondria such that the reducedactivity of ATP13A2 mutants may lead to mitochondrialdefects that contribute to neurodegeneration (Figure 1(b))[43] Fibroblasts from patients with KRS showed lowermitochondrial membrane potential and ATP synthesis ratesthan fibroblasts from healthy individuals [33] Cell culturesdeficient in ATP13A2 showed lower levels of autophagythan healthy cells leading to higher levels of reactiveoxygen species and concomitant oxidative stress [44]
Overexpressing ATP13A2 in neurons inhibited cadmium-induced mitochondrial fragmentation while silencingATP13A2 expression induced mitochondrial fragmentation[45] (Figure 1(b)) That same study further showed thatincreasing or decreasing ATP13A2 expression substantiallyshortened the neurites of primary midbrain DA neuronswithout affecting neurites of cortical neurons This maymean that the morphological and functional integrity of DAneurons depends on well-controlled ATP13A2 expression[45]
The available evidence suggests that ATP13A2 by sup-porting lysosomal andmitochondrial function helps preventthe 120572-synuclein aggregation associated with Parkinsonism
6 BioMed Research International
[46ndash49] The implication is that the ATP13A2 mutationslinked to KRS and other forms of PD are loss-of-functionmutations that reduce ATP13A2 activity sufficiently to induceneurodegeneration Future studies should examine in detailthe activity localization and binding partners of thesemutant proteins
42 ATP13A2 and Cation Accumulation ATP13A2 plays acritical role in the transmembrane transport of manganeseand zinc and perhaps of iron and cadmium as well [15]abnormal accumulation of any of these cations can causeneurodegeneration [41 50ndash52] Thus patients with PD havebeen reported to show elevated levels of manganese and zincin serum and cerebrospinal fluid [53ndash55] andmanganese andzinc exposure are significant environmental risk factors forPD [56 57] ATP13A2 helps protect cells from this toxicity byregulating the homeostasis ofmanganese and zinc in neurons[41 44 58 59] It may be that dysregulation of ATP13A2expression disrupts the homeostasis of manganese and zincin the brain leading to neurodegeneration
This possibility is consistent with the interpretation of theabnormal hypointensity in the putamina and caudate nucleiof patients with KRS in T2lowast diffuse MRI images as irondeposits (see Section 3) This finding led those authors topropose KRS with iron deposits as a distinct condition calledneurodegeneration with brain iron accumulation (NBIA)[20] Indeed iron accumulation was reported in the substan-tia nigra of PD patients [60] where it was particularly abun-dant in DA neurons [61] Administering the iron chelatordeferiprone to an animal model of PD induced by oxidativestress improved motor function and increased dopaminelevels in the striatum [62] In a pilot randomized clinical trialdouble-blind and placebo-controlled deferiprone showedsome ability to delay or reverse the progression of PD [62]
How mutations in ATP13A2may affect cation depositionis unclear We speculate that loss-of-function mutations inATP13A2 may work similarly to silencing of the PANK2gene which disrupts normal cation transfer and leads tomitochondrial and lysosomal dysfunction and ultimatelyto cation accumulation in the brain [63 64] In this wayATP13A2mutants may trigger deposition of the cations zincmanganese and iron leading to metal-induced oxidativedamage and ultimately causing decreases in glutathione per-oxidase activity glutathione (GSH) levels andmitochondrialComplex I activity as well as increases in levels of basal lipidperoxidation free radicals and glutamate [65ndash67] The netresult is significant neuronal loss that is the distinguishingpathological feature of PD
This proposed mechanism implies that regulating orrestoring the homeostasis of neurotoxic cations may be aneuroprotective therapy for patients with PD However onlytwo of the 37 PD patients with ATP13A2 mutations that wereviewed showed cation accumulation on T2lowast diffuse MRIimages (Table 2) and direct postmortem pathological evi-dence for metal accumulation in PD is lacking [20 33] Fur-ther studies are urgently needed to clarify whether ATP13A2mutations contribute to PD by increasing susceptibility tocation toxicity
5 ATP13A2 Mutations A Link betweenParkinsonism and NCLs
ATP13A2mutations have been identified not only in patientswith Parkinsonism but also in patients with neuronal ceroidlipofuscinoses (NCLs) [10] NCLs are a group of neurode-generative disorders that are also lysosomal storage diseasesClinical manifestations are seizures progressive cognitiveand motor decline and failing vision The pathologicalhallmark of NCLs is accumulation of autofluorescent lipopig-ment within neuronal lysosomes [68]
Recently the mutation c2429CgtG in exon 22 ofATP13A2 predicted to result in the amino acid substitutionpMet810Arg was identified in a Belgian family withNCLs [10] Affected individuals showed not only typicalNCL symptoms but also extrapyramidal involvementPostmortem pathological examination revealed extensivelipofuscin deposits in the cortex basal nuclei cerebellumand retinamdashbut not the white mattermdashand electronmicroscopy showed whorled lamellar inclusions typical ofNCLs [10] A link between ATP13A2 mutations and NCLpathogenesis is further supported by studies in animalmodels [69 70] In fact mice deficient in ATP13A2 exhibitedneuronal ceroid lipofuscinosis 120572-synuclein accumulationand age-dependent sensorimotor deficits suggesting that PDand NCLs share a pathogenic mechanism [71]
A shared disease pathwaymay help explain earlier reportsof individuals who demonstrate an ldquooverlappingrdquo neurode-generative syndrome combining Parkinsonism and NCLs[72ndash76] ATP13A2 is a lysosomal transport protein that helpsmaintain optimal pH in lysosomes [46] and ceramide ismetabolized in lysosomes [77] The apoptosis that appears tocause NCLs is associated with increased levels of ceramide[78 79] which have also been linked to 120572-synuclein deposi-tion whichmay contribute to PDpathogenesis [80] Itmay bethat ATP13A2 helps regulate ceramide metabolism such thatsignificant changes in ATP13A2 activitymay contribute to thepathogenesis of both PD and NCLs This model is similar tothat of the lysosomal storage disorder called Gaucher diseaseThe homozygousmutations in the 120573-glucocerebrosidase genethat cause Gaucher disease also increase risk of PD [81]Both diseases arise because lysosomal dysfunction leadsto excessive aggregation of substrates that normally aredegraded Analogously lysosomal dysfunction may underliethe clinically different neurodegenerative disorders of PD andNCLs
6 Summary
Much has been learned about the physiological functionsof ATP13A2 since mutations in the ATP13A2 gene werefirst linked to autosomal recessive familial KRS [7] Patientswith such mutations show onset at earlier ages than patientswith other forms of PD as well as some atypical clinicalsymptoms such as pyramidal degeneration supranuclearpalsy cognitive impairment and dystonia Studies in animalmodels of PD and in cultures of cells taken from patients withKRS and other types of PD suggest that ATP13A2 is important
BioMed Research International 7
for proper functioning of lysosomes and mitochondria andperhaps for clearance of divalent metals defects in any ofthese three processes are tightly associated with neurodegen-eration Nevertheless more studies are needed that directlyexamine how PD-associated mutations in ATP13A2 affectthe activity and localization of the protein and ultimatelythe integrity of these three processes ATP13A2 mutationsthat affect one of these processes lysosomal functioningmay simultaneously increase the risk of PD and NCLs Inotherwords these quite clinically different diseasesmay sharea mechanism of lysosomal dysfunction If further studiesvalidate the literature the ATP13A2 gene andor protein maybecome a suitable therapeutic target for treating both PD andNCLs
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Work by the authors related to this review was supportedby the Sichuan Key Project of Science and Technology (no2010SZ0086) and the National Natural Science Foundationof China (no 30700243)
References
[1] S Lesage and A Brice ldquoParkinsonrsquos disease from monogenicforms to genetic susceptibility factorsrdquo Human MolecularGenetics vol 18 no R1 pp R48ndashR59 2009
[2] V Bonifati ldquoGenetics of Parkinsonrsquos diseasemdashstate of the artrdquoParkinsonism amp Related Disorders vol 20 supplement 1 ppS23ndashS28 2014
[3] F Coppede ldquoGenetics and epigenetics of Parkinsonrsquos diseaserdquoScientific World Journal vol 2012 Article ID 489830 12 pages2012
[4] S Lesage E Lohmann F Tison F Durif A Durr and ABrice ldquoGene symbol PARK2 Disease parkinsonism juvenileautosomal recessiverdquoHuman genetics vol 123 no 1 article 1142008
[5] V Bonifati P Rizzu M J Van Baren et al ldquoMutations inthe DJ-1 gene associated with autosomal recessive early-onsetparkinsonismrdquo Science vol 299 no 5604 pp 256ndash259 2003
[6] Y Li H Tomiyama K Sato et al ldquoClinicogenetic study ofPINK1mutations in autosomal recessive early-onset parkinson-ismrdquo Neurology vol 64 no 11 pp 1955ndash1957 2005
[7] A Ramirez A Heimbach J Grundemann et al ldquoHeredi-tary parkinsonism with dementia is caused by mutations inATP13A2 encoding a lysosomal type 5 P-type ATPaserdquo NatureGenetics vol 38 no 10 pp 1184ndash1191 2006
[8] H Tomiyama H Yoshino K Ogaki et al ldquoPLA2G6 variant inParkinsons diseaserdquo Journal of Human Genetics vol 56 no 5pp 401ndash403 2011
[9] A Di Fonzo M C J Dekker P Montagna et al ldquoFBXO7mutations cause autosomal recessive early-onset parkinsonian-pyramidal syndromerdquo Neurology vol 72 no 3 pp 240ndash2452009
[10] J Bras A Verloes S A Schneider S E Mole and R J Guer-reiro ldquoMutation of the parkinsonism gene ATP13A2 causesneuronal ceroid-lipofuscinosisrdquo Human Molecular Geneticsvol 21 no 12 pp 2646ndash2650 2012
[11] A Di Fonzo H F Chien M Socal et al ldquoATP13A2 missensemutations in juvenile Parkinsonism and young onset Parkinsondiseaserdquo Neurology vol 68 no 19 pp 1557ndash1562 2007
[12] Y P Ning K Kanai H Tomiyama et al ldquoPARK9-linkedparkinsonism in eastern Asia mutation detection in ATP13A2and clinical phenotyperdquo Neurology vol 70 no 16 part 2 pp1491ndash1493 2008
[13] M Funayama H Tomiyama R M Wu et al ldquoRapid screeningof ATP13A2 variant with highresolution melting analysisrdquoMovement Disorders vol 25 no 14 pp 2434ndash2437 2010
[14] C H Lin E K Tan M L Chen et al ldquoNovel ATP13A2 variantassociated with Parkinson disease in Taiwan and SingaporerdquoNeurology vol 71 no 21 pp 1727ndash1732 2008
[15] C-M Chen C-H Lin H-F Juan et al ldquoATP13A2 variabilityin Taiwanese Parkinsonrsquos diseaserdquo American Journal of MedicalGenetics B Neuropsychiatric Genetics vol 156 no 6 pp 720ndash729 2011
[16] J Park PMehta A A Cooper et al ldquoPathogenic effects of novelmutations in the P-type ATPase ATP13A2 (PARK9) causingKufor-Rakeb syndrome a form of early-onset parkinsonismrdquoHuman Mutation vol 32 no 8 pp 956ndash964 2011
[17] L H Zhu X G Luo Y S Zhou et al ldquoLack of associationbetween three single nucleotide polymorphisms in the PARK9PARK15 and BST1 genes and Parkinsonrsquos disease in the north-ern Han Chinese populationrdquo Chinese Medical Journal vol 125no 4 pp 588ndash592 2012
[18] A Djarmati J Hagenah K Reetz et al ldquoATP13A2 variants inearly-onset Parkinsonrsquos disease patients and controlsrdquo Move-ment Disorders vol 24 no 14 pp 2104ndash2111 2009
[19] M Malakouti-Nejad G A Shahidi M Rohani et al ldquoIdenti-fication of pGln858lowast in ATP13A2 in two EOPD patients andpresentation of their clinical featuresrdquoNeuroscience Letters vol577 pp 106ndash111 2014
[20] S A Schneider C Paisan-Ruiz N P Quinn et al ldquoATP13A2mutations (PARK9) cause neurodegeneration with brain ironaccumulationrdquoMovement Disorders vol 25 no 8 pp 979ndash9842010
[21] C Y Fong A Rolfs T Schwarzbraun C Klein and F J KOrsquoCallaghan ldquoJuvenile parkinsonism associated with heterozy-gous frameshift ATP13A2 gene mutationrdquo European Journal ofPaediatric Neurology vol 15 no 3 pp 271ndash275 2011
[22] D Crosiers B Ceulemans B Meeus et al ldquoJuvenile dystonia-parkinsonism and dementia caused by a novel ATP13A2frameshift mutationrdquo Parkinsonism and Related Disorders vol17 no 2 pp 135ndash138 2011
[23] H Eiberg L Hansen L Korbo et al ldquoNovel mutation inATP13A2 widens the spectrum of Kufor-Rakeb syndrome(PARK9)rdquo Clinical Genetics vol 82 no 3 pp 256ndash263 2012
[24] L Santoro G J Breedveld F Manganelli et al ldquoNovelATP13A2(PARK9) homozygous mutation in a family with markedphenotype variabilityrdquo Neurogenetics vol 12 no 1 pp 33ndash392011
[25] Q Z Fei L Cao Q Xiao et al ldquoLack of association betweenATP13A2 Ala746Thr variant and Parkinsons disease in Hanpopulation of mainland Chinardquo Neuroscience Letters vol 475no 2 pp 61ndash63 2010
8 BioMed Research International
[26] X Y Mao J M Burgunder Z J Zhang et al ldquoATP13A2G2236A variant is rare in patients with early-onset Parkinsonrsquosdisease and familial Parkinsonrsquos disease from mainland ChinardquoParkinsonism and Related Disorders vol 16 no 3 pp 235ndash2362010
[27] A Y Y Chan L Baum N L S Tang et al ldquoThe role ofthe Ala746Thr variant in the ATP13A2 gene among Chinesepatients with Parkinsonrsquos diseaserdquo Journal of Clinical Neuro-science vol 20 no 5 pp 761ndash762 2013
[28] H Darvish A Movafagh M D Omrani et al ldquoDetectionof copy number changes in genes associated with Parkinsonrsquosdisease in Iranian patientsrdquo Neuroscience Letters vol 551 pp75ndash78 2013
[29] C Vilarino-Guell A I Soto S J Lincoln et al ldquoATP13A2variability in Parkinson diseaserdquo Human Mutation vol 30 no3 pp 406ndash410 2009
[30] A Rakovic B Stiller A Djarmati et al ldquoGenetic associationstudy of the P-type ATPase ATP13A2 in late-onset ParkinsonrsquosdiseaserdquoMovement Disorders vol 24 no 3 pp 429ndash433 2009
[31] A S Najim Al-Din A Wriekat A Mubaidin M Dasoukiand M Hiari ldquoPallido-pyramidal degeneration supranuclearupgaze paresis and dementia Kufor-Rakeb syndromerdquo ActaNeurologica Scandinavica vol 89 no 5 pp 347ndash352 1994
[32] D R Williams A Hadeed A S Najim al-Din A Wreikatand A J Lees ldquoKufor Rakeb disease autosomal recessivelevodopa-responsive Parkinsonism with pyramidal degenera-tion supranuclear gaze palsy and dementiardquoMovement Disor-ders vol 20 no 10 pp 1264ndash1271 2005
[33] M I Behrens N Bruggemann P Chana et al ldquoClinicalspectrum of Kufor-Rakeb syndrome in the Chilean kindredwith ATP13A2 mutationsrdquoMovement Disorders vol 25 no 12pp 1929ndash1937 2010
[34] P J Schultheis T T Hagen K K OrsquoToole et al ldquoCharacteriza-tion of the P5 subfamily of P-type transport ATPases in micerdquoBiochemical and Biophysical Research Communications vol 323no 3 pp 731ndash738 2004
[35] B Schroder CWrocklage C Pan et al ldquoIntegral and associatedlysosomal membrane proteinsrdquo Traffic vol 8 no 12 pp 1676ndash1686 2007
[36] H Matsui F Sato S Sato et al ldquoATP13A2 deficiency inducesa decrease in cathepsin D activity fingerprint-like inclusionbody formation and selective degeneration of dopaminergicneuronsrdquo FEBS Letters vol 587 no 9 pp 1316ndash1325 2013
[37] B Dehay A Ramirez M Martinez-Vicente et al ldquoLoss of P-type ATPase ATP13A2PARK9 function induces general lyso-somal deficiency and leads to Parkinson disease neurodegen-erationrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 109 no 24 pp 9611ndash9616 2012
[38] K E Murphy L Cottle A M Gysbers A A Cooper and GM Halliday ldquoATP13A2 (PARK9) protein levels are reduced inbrain tissue of cases with Lewy bodiesrdquo Acta NeuropathologicaCommunications vol 1 article 11 2013
[39] G K Tofaris ldquoLysosome-dependent pathways as a unifyingtheme in Parkinsonrsquos diseaserdquo Movement Disorders vol 27 no11 pp 1364ndash1369 2012
[40] S M Kong B K Chan J S Park et al ldquoParkinsonrsquos disease-linked human PARK9 ATP13A2 maintains zinc homeosta-sis and promotes 120572-Synuclein externalization via exosomesrdquoHuman Molecular Genetics vol 23 no 11 pp 2816ndash2833 2014
[41] A D Gitler A Chesi M L Geddie et al ldquo120572-Synuclein ispart of a diverse and highly conserved interaction network that
includes PARK9 and manganese toxicityrdquo Nature Genetics vol41 no 3 pp 308ndash315 2009
[42] M Usenovic E Tresse J R Mazzulli J P Taylor and DKrainc ldquoDeficiency ofATP13A2 leads to lysosomal dysfunction120572-synuclein accumulation and neurotoxicityrdquo The Journal ofNeuroscience vol 32 no 12 pp 4240ndash4246 2012
[43] J S Park B Koentjoro D Veivers A Mackay-Sim and C MSue ldquoParkinsonrsquos disease-associated human ATP13A2 (PARK9)deficiency causes zinc dyshomeostasis andmitochondrial dys-functionrdquo Human Molecular Genetics vol 23 no 11 pp 2802ndash2815 2014
[44] A M Gusdon J Zhu B van Houten and C T ChuldquoATP13A2 regulates mitochondrial bioenergetics throughmacroautophagyrdquo Neurobiology of Disease vol 45 no 3 pp962ndash972 2012
[45] D Ramonet A Podhajska K Stafa et al ldquoPARK9-associatedATP13A2 localizes to intracellular acidic vesicles and regulatescation homeostasis and neuronal integrityrdquo Human MolecularGenetics vol 21 no 8 pp 1725ndash1743 2012
[46] R A Nixon D S Yang and J H Lee ldquoNeurodegenerativelysosomal disorders a continuum from development to lateagerdquo Autophagy vol 4 no 5 pp 590ndash599 2008
[47] B Dehay M Martinez-Vicente G A Caldwell et al ldquoLysoso-mal impairment in Parkinsonrsquos diseaserdquo Movement Disordersvol 28 no 6 pp 725ndash732 2013
[48] C W Olanow and P Brundin ldquoParkinsonrsquos disease and alphasynuclein is Parkinsonrsquos disease a prion-like disorderrdquo Move-ment Disorders vol 28 no 1 pp 31ndash40 2013
[49] J Bove M Martınez-Vicente and M Vila ldquoFighting neu-rodegeneration with rapamycin mechanistic insightsrdquo NatureReviews Neuroscience vol 12 no 8 pp 437ndash452 2011
[50] K Schmidt D M Wolfe B Stiller and D A Pearce ldquoCd2+Mn2+ Ni2+ and Se2+ toxicity to Saccharomyces cerevisiaelacking YPK9p the orthologue of human ATP13A2rdquo Biochem-ical and Biophysical Research Communications vol 383 no 2pp 198ndash202 2009
[51] P G Mastroberardino E K Hoffman M P Horowitz et al ldquoAnovel transferrinTfR2-mediated mitochondrial iron transportsystem is disrupted in Parkinsonrsquos diseaserdquo Neurobiology ofDisease vol 34 no 3 pp 417ndash431 2009
[52] C T Sheline J Zhu W Zhang C Shi and A Cai ldquoMitochon-drial inhibitor models of Huntingtonrsquos disease and Parkinsonrsquosdisease induce zinc accumulation and are attenuated by inhibi-tion of zinc neurotoxicity in vitro or in vivordquoNeurodegenerativeDiseases vol 11 no 1 pp 49ndash58 2013
[53] T Fukushima X Tan Y Luo and H Kanda ldquoSerum vitaminsand heavy metals in blood and urine and the correlationsamong them in parkinsonrsquos disease patients inChinardquoNeuroepi-demiology vol 36 no 4 pp 240ndash244 2011
[54] I Hozumi T Hasegawa A Honda et al ldquoPatterns of levelsof biological metals in CSF differ among neurodegenerativediseasesrdquo Journal of the Neurological Sciences vol 303 no 1-2pp 95ndash99 2011
[55] F J Jimenez-Jimenez P Fernandez-Calle M Martınez-Vanaclocha et al ldquoSerum levels of zinc and copper in patientswith Parkinsonrsquos diseaserdquo Journal of the Neurological Sciencesvol 112 no 1-2 pp 30ndash33 1992
[56] T R Guilarte ldquoManganese and Parkinsonrsquos disease a criticalreview and new findingsrdquo Environmental Health Perspectivesvol 118 no 8 pp 1071ndash1080 2010
BioMed Research International 9
[57] P Pals B van Everbroeck B Grubben et al ldquoCase-controlstudy of environmental risk factors for Parkinsonrsquos disease inBelgiumrdquo European Journal of Epidemiology vol 18 no 12 pp1133ndash1142 2003
[58] G Rentschler L Covolo A Ahmadi Haddad R G LucchiniS Zoni and K Broberg ldquoATP13A2 (PARK9) polymorphismsinfluence the neurotoxic effects of manganeserdquo NeuroToxicol-ogy vol 33 no 4 pp 697ndash702 2012
[59] J Tan T Zhang L Jiang et al ldquoRegulation of intracellularmanganese homeostasis by Kufor-Rakeb syndrome-associatedATP13A2 proteinrdquo Journal of Biological Chemistry vol 286 no34 pp 29654ndash29662 2011
[60] D Berg andHHochstrasser ldquoIronmetabolism in parkinsoniansyndromesrdquo Movement Disorders vol 21 no 9 pp 1299ndash13102006
[61] A E Oakley J F Collingwood J Dobson et al ldquoIndividualdopaminergic neurons show raised iron levels in Parkinsondiseaserdquo Neurology vol 68 no 21 pp 1820ndash1825 2007
[62] D Devos C Moreau and J C Devedjian ldquoTargeting chelatableiron as a therapeutic modality in Parkinsonrsquos diseaserdquo Antioxi-dants and Redox Signaling vol 21 no 2 pp 195ndash210 2014
[63] M Poli M Derosas S Luscieti et al ldquoPantothenate kinase-2 (Pank2) silencing causes cell growth reduction cell-specificferroportin upregulation and iron deregulationrdquo Neurobiologyof Disease vol 39 no 2 pp 204ndash210 2010
[64] T Tsunemi and D Krainc ldquoZn2+ dyshomeostasis caused by lossof ATP13A2PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulationrdquo Human Molecular Genetics vol 23no 11 pp 2791ndash2801 2014
[65] J Xu E Marzetti A Y Seo J Kim T A Prolla and CLeeuwenburgh ldquoThe emerging role of iron dyshomeostasis inthe mitochondrial decay of agingrdquo Mechanisms of Ageing andDevelopment vol 131 no 7-8 pp 487ndash493 2010
[66] M B H Youdim and P Riederer ldquoThe role of iron in senescenceof dopaminergic neurons in Parkinsonrsquos diseaserdquo Journal ofNeural Transmission Supplement no 40 pp 57ndash67 1993
[67] P Karki E Lee and M Aschner ldquoManganese neurotoxicity afocus on glutamate transportersrdquo Annals of Occupational andEnvironmental Medicine vol 25 no 1 article 4 2013
[68] H H Goebel L Gerhard E Kominami and M Hal-tia ldquoNeuronal ceroid-lipofuscinosismdashlate-infantile or Jansky-Bielschowsky typemdashrevisitedrdquo Brain Pathology vol 6 no 3 pp225ndash228 1996
[69] A Wohlke U Philipp P Bock et al ldquoA one base pair deletionin the canine ATP13A2 gene causes exon skipping and late-onset neuronal ceroid lipofuscinosis in the Tibetan terrierrdquoPLoS Genetics vol 7 no 10 Article ID e1002304 2011
[70] F H G Farias R Zeng G S Johnson et al ldquoA truncatingmuta-tion in ATP13A2 is responsible for adult-onset neuronal ceroidlipofuscinosis in Tibetan terriersrdquo Neurobiology of Disease vol42 no 3 pp 468ndash474 2011
[71] P J Schultheis S M Fleming A K Clippinger et al ldquoAtp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis limited120572-synuclein accumulation and age-dependent sensorimotordeficitsrdquo Human Molecular Genetics vol 22 no 10 pp 2067ndash2082 2013
[72] J G Burneo T Arnold C A Palmer R I Kuzniecky SJ Oh and E Faught ldquoAdult-onset neuronal ceroid lipofusci-nosis (Kufs disease) with autosomal dominant inheritance inAlabamardquo Epilepsia vol 44 no 6 pp 841ndash846 2003
[73] S F Berkovic S Carpenter F Andermann E Andermann andL S Wolfe ldquoKufsrsquo disease a critical reappraisalrdquo Brain vol 111no 1 part 1 pp 27ndash62 1988
[74] P C G Nijssen E Brusse A C M Leyten J J Martin JL J M Teepen and R A C Roos ldquoAutosomal dominantadult neuronal ceroid lipofuscinosis parkinsonism due to bothstriatal and nigral dysfunctionrdquoMovement Disorders vol 17 no3 pp 482ndash487 2002
[75] P E M Taschner N de Vos A D Thompson et al ldquoChro-mosome 16 microdeletion in a patient with juvenile neuronalceroid lipofuscinosis (Batten disease)rdquoThe American Journal ofHuman Genetics vol 56 no 3 pp 663ndash668 1995
[76] A Y Lavrov E S Ilyna E Y Zakharova A M Boukina andS V Tishkanina ldquoThe first three Russian cases of classical late-infantile neuronal ceroid lipofuscinosisrdquo European Journal ofPaediatric Neurology vol 6 no 3 pp 161ndash164 2002
[77] J Bras A Singleton M R Cookson and J Hardy ldquoEmerg-ing pathways in genetic Parkinsonrsquos disease potential role ofceramide metabolism in Lewy body diseaserdquo FEBS Journal vol275 no 23 pp 5767ndash5773 2008
[78] S El Haddad M Khoury M Daoud et al ldquoCLN5 and CLN8protein association with ceramide synthase biochemical andproteomic approachesrdquoElectrophoresis vol 33 no 24 pp 3798ndash3809 2012
[79] D Persaud-Sawin T Mousallem C Wang A Zucker E Kom-inami and R N Boustany ldquoNeuronal ceroid lipofuscinosis acommon pathwayrdquo Pediatric Research vol 61 no 2 pp 146ndash152 2007
[80] T J van Ham K L Thijssen R Breitling R M W Hofstra RH A Plasterk and E A A Nollen ldquoC elegansmodel identifiesgenetic modifiers of 120572-synuclein inclusion formation duringagingrdquo PLoS Genetics vol 4 no 3 Article ID e1000027 2008
[81] A Halperin D Elstein and A Zimran ldquoIncreased incidenceof Parkinson disease among relatives of patients with Gaucherdiseaserdquo Blood Cells Molecules and Diseases vol 36 no 3 pp426ndash428 2006
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
International Journal of
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BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
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Parkinsonrsquos Disease
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Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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4 BioMed Research International
Table2Clinicalfeatures
ofpatie
ntsw
ithParkinsonrsquos
diseasea
ndmutations
intheA
TP13A2
gene
Ref
Internalcode
Mutation
Cou
ntry
oforigin
AO(years)
GFH
ISMS
MC
SUP
DYS
CDH
BSRe
spon
seto
levodo
paIm
agingfin
ding
s
[26]
V44
1632
1653du
p22(552LeufsX
788)
Jordan
12M
+B
MR
RB
RPI
++minus
++
++
Diffusea
troph
y(M
RI)
V48
Jordan
15M
+B
RB
RPI
++
++
++
+Diffusea
troph
y(M
RI)
V49
Jordan
13M
+MR
RB
RPI
+minus
++
++
+Diffusea
troph
y(M
RI)
V53
Jordan
12F
+B
BR
PI+minus
++
++
+NR
[1]
II-8
c3057delC(p10
19GfsX1021)
c1306+
5GgtA(pG399L4
35del)
Chile
18M
+BR
FTB
R+
+NR
++
+Never
tried
Enlarged
sulci(CT
)
II-9
Chile
17M
+BR
BR
TB
RPI
+minus
NR
++minus
minusMild
diffusea
troph
ycaud
ate
hypo
intensity
(MRI)
II-10
Chile
15F
+B
FBR
TB
RPI
++
NR
+minus
+minus
NR
II-11
Chile
12M
+FBR
TB
RPI
++
NR
++
+minus
Diffusea
troph
y(C
T)
[11]
BR-304
2c1510GgtC(G
ly504A
rg)
Brazil
12Mminus
BB
RPI
++
NR
++
++
Diffusea
troph
y(C
T)VE2
9c3
5CgtT(Th
r12M
et)
Italy
30M
+NA
TB
RPI
NR
++minusminus
++
NR
PK-69-1
c1597CgtA(G
ly533A
rg)
Italy
40M
+NA
BR
PINR
++minus
++
+NR
[18]
L-1349
c746
CgtT(A
la249V
al)
Germany
31Fminus
TTB
RPI
NR
+minus
NR
+minus
+Normal(M
RI)
L-1928
c844
AgtT(Ser282C
ys)
Norway
20Mminus
PIR
PINR
+minus
NRminus
++
Normal(M
RI)
L-324
c1346GgtA(A
rg44
9Gln)
Iran
36Mminus
TB
RPI
NR
+minus
NR
++
+Cerebralatro
phy(C
T)P-55
c2939GgtA(A
rg980H
is)Serbia
35Fminus
PTTB
RPI
NR
+minus
NR
++
+Normal
[20]
NR
c11031104
insG
A(pTh
r367fsX2
9)Pakista
n16
Mminus
BMR
BR
PIminus
++
++
++
Diffusea
troph
y(M
RI)
[22]
II-3
c27422743delTT(pF851C
fsX8
56)
Afghanista
n10
Mminus
BMR
BR
PI+
++
+minus
++
Diffusea
troph
ybilateralhypo
intensity
inpu
taminaa
ndcaud
aten
uclei(MRI)
[21]
NR
c11081120del13
(pArg370fsX
390)
Lithuania
6Mminus
Dysarthria
DYS
TB
RPI
NRminus
+minus
NRminus
+Normal(M
RI)
[23]
VI-1
c2473CgtAA(pLeu825AsnfsX3
2)
Greenland
27F
+FA
NR
NR
NR
NR
++
+NR
Diffusea
troph
y(M
RI)
VI-6
Greenland
24M
+Weakn
ess
NR
NR
NR
++
++
NR
Diffusea
troph
y(M
RI)
V-1
Greenland
12M
+T
BR
++
++
++
NR
Normal(M
RI)
V-3
Greenland
10F
+CD
TB
Rminusminusminusminus
+minus
NR
NR
V-5
Greenland
29F
+GD
PI+
+minus
+minus
+NR
Diffusea
troph
y(M
RI)
V-9
Greenland
15F
+B
MR
TB
R+
NR
NR
+minus
NR
NR
NR
[19]
X4015
c2762CgtT(pGln858lowast
)Iran
14F
+Motor
defect
TB
RPI
NR
++
+minus
++
Diffusea
troph
y(M
RI)
X404
1Iran
10M
+B
TB
RPI
NR
++
+minus
++
Diffusea
troph
y(M
RI)
R104
2Iran
30M
+NR
TB
RPI
NR
NR
NR
NR
NR
NR
+NR
[24]
NAPO
6c2
629GgtA(G
ly877A
rg)
Italy
10Mminus
GD
BR
PI+
++
+minus
++
Diffusea
troph
y(M
RI)
[12]
Ac5
46Cgt
A(Phe182L
eu)
Japan
22Fminus
GD
TB
RPI
++
++
++
+Diffusea
troph
y(M
RI)
[14]
F37
c2236GgtA(A
la746Th
r)Ch
ina
53Fminus
NA
TB
Rminusminus
+minus
NR
++
Normal(M
RI)
EK1
China
50Mminus
NA
TB
RPIminusminus
+minus
NR
++
Normal(M
RI)
Y56
China
39Mminus
NA
TB
RPIminusminus
+minus
NR
++
Normal(M
RI)
[15]
H1288
c3274AgtG(pGly1014Ser)
China
48Fminus
NA
TB
RPI
NR
NR
NR
NR
NR
NR
+Normal(M
RI)
H496
c2236GgtA(A
la746Th
r)Ch
ina
49Mminus
NA
TB
RPI
NR
NR
NR
NR
NR
NR
+NR
H2120
c2236GgtA(A
la746Th
r)Ch
ina
51Fminus
NA
TB
RPI
NR
NR
NR
NR
NR
NR
+NR
[16]
NR
c3176CgtG(Leu1059Arg)
c3253delC(L1085wfsX1088)
China
17M
+A
BR
++
+NRminus
++
Normal(M
RI)
NR
China
17F
+AD
BR
++
+NRminus
++
Normal(M
RI)
Aanx
ietyA
Oage
ofon
setB
bradykinesiaB
SBa
binski
sign
CDcognitiv
edysfu
nctio
nDd
epression
DYS
dystoniaF
femaleFA
fatigueF
Hfam
ilyhisto
ryG
genderGDgaitd
isturbanceISinitia
lsymptom
Mm
aleMC
myoclo
nusMSmotor
symptom
NR
notreportedPIposturalinstabilityPT
posturaltremorR
rigidity
SUP
supranuclear
upgaze
palsy
Ttremor
BioMed Research International 5
ATP13A2 ProteaseX
CD63120572-Synuclein
Exosome
Degradation
LysosomeX XXXX
XXXXX
XXXX
MVBsAutophagosome
Intracellular
Externalisation
Extracellular
(a)
ATP13A2++ ATP13A2minusminus
ATP ATP
Degeneration
Mitochondria
ATPATP
Ca2+
ROS
(b)
Figure 1 Model of how ATP13A2 expression may affect lysosomes and mitochondria to prevent neurodegeneration (a) After 120572-synucleinhas been internalized by autophagosomes it can be immediately degraded in lysosomes containing ATP13A2 or secreted out of the cell viamultivesicular bodies (MVBs) also containing ATP13A2 Both routes prevent intracellular accumulation of 120572-synuclein (b) Knocking outATP13A2 expression in neurons leads to mitochondrial defects resulting in higher intracellular levels of reactive oxygen species (ROS) andCa2+ both of which contribute to neurodegeneration
ATP13A2 interacts preferentially with 120572-synuclein consistentwith a recent study showing that ATP13A2 colocalized with120572-synuclein in Lewy bodies but not with 120573-amyloid [38]
In addition to ensuring proper lysosomal functionATP13A2 may work in mitochondria such that the reducedactivity of ATP13A2 mutants may lead to mitochondrialdefects that contribute to neurodegeneration (Figure 1(b))[43] Fibroblasts from patients with KRS showed lowermitochondrial membrane potential and ATP synthesis ratesthan fibroblasts from healthy individuals [33] Cell culturesdeficient in ATP13A2 showed lower levels of autophagythan healthy cells leading to higher levels of reactiveoxygen species and concomitant oxidative stress [44]
Overexpressing ATP13A2 in neurons inhibited cadmium-induced mitochondrial fragmentation while silencingATP13A2 expression induced mitochondrial fragmentation[45] (Figure 1(b)) That same study further showed thatincreasing or decreasing ATP13A2 expression substantiallyshortened the neurites of primary midbrain DA neuronswithout affecting neurites of cortical neurons This maymean that the morphological and functional integrity of DAneurons depends on well-controlled ATP13A2 expression[45]
The available evidence suggests that ATP13A2 by sup-porting lysosomal andmitochondrial function helps preventthe 120572-synuclein aggregation associated with Parkinsonism
6 BioMed Research International
[46ndash49] The implication is that the ATP13A2 mutationslinked to KRS and other forms of PD are loss-of-functionmutations that reduce ATP13A2 activity sufficiently to induceneurodegeneration Future studies should examine in detailthe activity localization and binding partners of thesemutant proteins
42 ATP13A2 and Cation Accumulation ATP13A2 plays acritical role in the transmembrane transport of manganeseand zinc and perhaps of iron and cadmium as well [15]abnormal accumulation of any of these cations can causeneurodegeneration [41 50ndash52] Thus patients with PD havebeen reported to show elevated levels of manganese and zincin serum and cerebrospinal fluid [53ndash55] andmanganese andzinc exposure are significant environmental risk factors forPD [56 57] ATP13A2 helps protect cells from this toxicity byregulating the homeostasis ofmanganese and zinc in neurons[41 44 58 59] It may be that dysregulation of ATP13A2expression disrupts the homeostasis of manganese and zincin the brain leading to neurodegeneration
This possibility is consistent with the interpretation of theabnormal hypointensity in the putamina and caudate nucleiof patients with KRS in T2lowast diffuse MRI images as irondeposits (see Section 3) This finding led those authors topropose KRS with iron deposits as a distinct condition calledneurodegeneration with brain iron accumulation (NBIA)[20] Indeed iron accumulation was reported in the substan-tia nigra of PD patients [60] where it was particularly abun-dant in DA neurons [61] Administering the iron chelatordeferiprone to an animal model of PD induced by oxidativestress improved motor function and increased dopaminelevels in the striatum [62] In a pilot randomized clinical trialdouble-blind and placebo-controlled deferiprone showedsome ability to delay or reverse the progression of PD [62]
How mutations in ATP13A2may affect cation depositionis unclear We speculate that loss-of-function mutations inATP13A2 may work similarly to silencing of the PANK2gene which disrupts normal cation transfer and leads tomitochondrial and lysosomal dysfunction and ultimatelyto cation accumulation in the brain [63 64] In this wayATP13A2mutants may trigger deposition of the cations zincmanganese and iron leading to metal-induced oxidativedamage and ultimately causing decreases in glutathione per-oxidase activity glutathione (GSH) levels andmitochondrialComplex I activity as well as increases in levels of basal lipidperoxidation free radicals and glutamate [65ndash67] The netresult is significant neuronal loss that is the distinguishingpathological feature of PD
This proposed mechanism implies that regulating orrestoring the homeostasis of neurotoxic cations may be aneuroprotective therapy for patients with PD However onlytwo of the 37 PD patients with ATP13A2 mutations that wereviewed showed cation accumulation on T2lowast diffuse MRIimages (Table 2) and direct postmortem pathological evi-dence for metal accumulation in PD is lacking [20 33] Fur-ther studies are urgently needed to clarify whether ATP13A2mutations contribute to PD by increasing susceptibility tocation toxicity
5 ATP13A2 Mutations A Link betweenParkinsonism and NCLs
ATP13A2mutations have been identified not only in patientswith Parkinsonism but also in patients with neuronal ceroidlipofuscinoses (NCLs) [10] NCLs are a group of neurode-generative disorders that are also lysosomal storage diseasesClinical manifestations are seizures progressive cognitiveand motor decline and failing vision The pathologicalhallmark of NCLs is accumulation of autofluorescent lipopig-ment within neuronal lysosomes [68]
Recently the mutation c2429CgtG in exon 22 ofATP13A2 predicted to result in the amino acid substitutionpMet810Arg was identified in a Belgian family withNCLs [10] Affected individuals showed not only typicalNCL symptoms but also extrapyramidal involvementPostmortem pathological examination revealed extensivelipofuscin deposits in the cortex basal nuclei cerebellumand retinamdashbut not the white mattermdashand electronmicroscopy showed whorled lamellar inclusions typical ofNCLs [10] A link between ATP13A2 mutations and NCLpathogenesis is further supported by studies in animalmodels [69 70] In fact mice deficient in ATP13A2 exhibitedneuronal ceroid lipofuscinosis 120572-synuclein accumulationand age-dependent sensorimotor deficits suggesting that PDand NCLs share a pathogenic mechanism [71]
A shared disease pathwaymay help explain earlier reportsof individuals who demonstrate an ldquooverlappingrdquo neurode-generative syndrome combining Parkinsonism and NCLs[72ndash76] ATP13A2 is a lysosomal transport protein that helpsmaintain optimal pH in lysosomes [46] and ceramide ismetabolized in lysosomes [77] The apoptosis that appears tocause NCLs is associated with increased levels of ceramide[78 79] which have also been linked to 120572-synuclein deposi-tion whichmay contribute to PDpathogenesis [80] Itmay bethat ATP13A2 helps regulate ceramide metabolism such thatsignificant changes in ATP13A2 activitymay contribute to thepathogenesis of both PD and NCLs This model is similar tothat of the lysosomal storage disorder called Gaucher diseaseThe homozygousmutations in the 120573-glucocerebrosidase genethat cause Gaucher disease also increase risk of PD [81]Both diseases arise because lysosomal dysfunction leadsto excessive aggregation of substrates that normally aredegraded Analogously lysosomal dysfunction may underliethe clinically different neurodegenerative disorders of PD andNCLs
6 Summary
Much has been learned about the physiological functionsof ATP13A2 since mutations in the ATP13A2 gene werefirst linked to autosomal recessive familial KRS [7] Patientswith such mutations show onset at earlier ages than patientswith other forms of PD as well as some atypical clinicalsymptoms such as pyramidal degeneration supranuclearpalsy cognitive impairment and dystonia Studies in animalmodels of PD and in cultures of cells taken from patients withKRS and other types of PD suggest that ATP13A2 is important
BioMed Research International 7
for proper functioning of lysosomes and mitochondria andperhaps for clearance of divalent metals defects in any ofthese three processes are tightly associated with neurodegen-eration Nevertheless more studies are needed that directlyexamine how PD-associated mutations in ATP13A2 affectthe activity and localization of the protein and ultimatelythe integrity of these three processes ATP13A2 mutationsthat affect one of these processes lysosomal functioningmay simultaneously increase the risk of PD and NCLs Inotherwords these quite clinically different diseasesmay sharea mechanism of lysosomal dysfunction If further studiesvalidate the literature the ATP13A2 gene andor protein maybecome a suitable therapeutic target for treating both PD andNCLs
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Work by the authors related to this review was supportedby the Sichuan Key Project of Science and Technology (no2010SZ0086) and the National Natural Science Foundationof China (no 30700243)
References
[1] S Lesage and A Brice ldquoParkinsonrsquos disease from monogenicforms to genetic susceptibility factorsrdquo Human MolecularGenetics vol 18 no R1 pp R48ndashR59 2009
[2] V Bonifati ldquoGenetics of Parkinsonrsquos diseasemdashstate of the artrdquoParkinsonism amp Related Disorders vol 20 supplement 1 ppS23ndashS28 2014
[3] F Coppede ldquoGenetics and epigenetics of Parkinsonrsquos diseaserdquoScientific World Journal vol 2012 Article ID 489830 12 pages2012
[4] S Lesage E Lohmann F Tison F Durif A Durr and ABrice ldquoGene symbol PARK2 Disease parkinsonism juvenileautosomal recessiverdquoHuman genetics vol 123 no 1 article 1142008
[5] V Bonifati P Rizzu M J Van Baren et al ldquoMutations inthe DJ-1 gene associated with autosomal recessive early-onsetparkinsonismrdquo Science vol 299 no 5604 pp 256ndash259 2003
[6] Y Li H Tomiyama K Sato et al ldquoClinicogenetic study ofPINK1mutations in autosomal recessive early-onset parkinson-ismrdquo Neurology vol 64 no 11 pp 1955ndash1957 2005
[7] A Ramirez A Heimbach J Grundemann et al ldquoHeredi-tary parkinsonism with dementia is caused by mutations inATP13A2 encoding a lysosomal type 5 P-type ATPaserdquo NatureGenetics vol 38 no 10 pp 1184ndash1191 2006
[8] H Tomiyama H Yoshino K Ogaki et al ldquoPLA2G6 variant inParkinsons diseaserdquo Journal of Human Genetics vol 56 no 5pp 401ndash403 2011
[9] A Di Fonzo M C J Dekker P Montagna et al ldquoFBXO7mutations cause autosomal recessive early-onset parkinsonian-pyramidal syndromerdquo Neurology vol 72 no 3 pp 240ndash2452009
[10] J Bras A Verloes S A Schneider S E Mole and R J Guer-reiro ldquoMutation of the parkinsonism gene ATP13A2 causesneuronal ceroid-lipofuscinosisrdquo Human Molecular Geneticsvol 21 no 12 pp 2646ndash2650 2012
[11] A Di Fonzo H F Chien M Socal et al ldquoATP13A2 missensemutations in juvenile Parkinsonism and young onset Parkinsondiseaserdquo Neurology vol 68 no 19 pp 1557ndash1562 2007
[12] Y P Ning K Kanai H Tomiyama et al ldquoPARK9-linkedparkinsonism in eastern Asia mutation detection in ATP13A2and clinical phenotyperdquo Neurology vol 70 no 16 part 2 pp1491ndash1493 2008
[13] M Funayama H Tomiyama R M Wu et al ldquoRapid screeningof ATP13A2 variant with highresolution melting analysisrdquoMovement Disorders vol 25 no 14 pp 2434ndash2437 2010
[14] C H Lin E K Tan M L Chen et al ldquoNovel ATP13A2 variantassociated with Parkinson disease in Taiwan and SingaporerdquoNeurology vol 71 no 21 pp 1727ndash1732 2008
[15] C-M Chen C-H Lin H-F Juan et al ldquoATP13A2 variabilityin Taiwanese Parkinsonrsquos diseaserdquo American Journal of MedicalGenetics B Neuropsychiatric Genetics vol 156 no 6 pp 720ndash729 2011
[16] J Park PMehta A A Cooper et al ldquoPathogenic effects of novelmutations in the P-type ATPase ATP13A2 (PARK9) causingKufor-Rakeb syndrome a form of early-onset parkinsonismrdquoHuman Mutation vol 32 no 8 pp 956ndash964 2011
[17] L H Zhu X G Luo Y S Zhou et al ldquoLack of associationbetween three single nucleotide polymorphisms in the PARK9PARK15 and BST1 genes and Parkinsonrsquos disease in the north-ern Han Chinese populationrdquo Chinese Medical Journal vol 125no 4 pp 588ndash592 2012
[18] A Djarmati J Hagenah K Reetz et al ldquoATP13A2 variants inearly-onset Parkinsonrsquos disease patients and controlsrdquo Move-ment Disorders vol 24 no 14 pp 2104ndash2111 2009
[19] M Malakouti-Nejad G A Shahidi M Rohani et al ldquoIdenti-fication of pGln858lowast in ATP13A2 in two EOPD patients andpresentation of their clinical featuresrdquoNeuroscience Letters vol577 pp 106ndash111 2014
[20] S A Schneider C Paisan-Ruiz N P Quinn et al ldquoATP13A2mutations (PARK9) cause neurodegeneration with brain ironaccumulationrdquoMovement Disorders vol 25 no 8 pp 979ndash9842010
[21] C Y Fong A Rolfs T Schwarzbraun C Klein and F J KOrsquoCallaghan ldquoJuvenile parkinsonism associated with heterozy-gous frameshift ATP13A2 gene mutationrdquo European Journal ofPaediatric Neurology vol 15 no 3 pp 271ndash275 2011
[22] D Crosiers B Ceulemans B Meeus et al ldquoJuvenile dystonia-parkinsonism and dementia caused by a novel ATP13A2frameshift mutationrdquo Parkinsonism and Related Disorders vol17 no 2 pp 135ndash138 2011
[23] H Eiberg L Hansen L Korbo et al ldquoNovel mutation inATP13A2 widens the spectrum of Kufor-Rakeb syndrome(PARK9)rdquo Clinical Genetics vol 82 no 3 pp 256ndash263 2012
[24] L Santoro G J Breedveld F Manganelli et al ldquoNovelATP13A2(PARK9) homozygous mutation in a family with markedphenotype variabilityrdquo Neurogenetics vol 12 no 1 pp 33ndash392011
[25] Q Z Fei L Cao Q Xiao et al ldquoLack of association betweenATP13A2 Ala746Thr variant and Parkinsons disease in Hanpopulation of mainland Chinardquo Neuroscience Letters vol 475no 2 pp 61ndash63 2010
8 BioMed Research International
[26] X Y Mao J M Burgunder Z J Zhang et al ldquoATP13A2G2236A variant is rare in patients with early-onset Parkinsonrsquosdisease and familial Parkinsonrsquos disease from mainland ChinardquoParkinsonism and Related Disorders vol 16 no 3 pp 235ndash2362010
[27] A Y Y Chan L Baum N L S Tang et al ldquoThe role ofthe Ala746Thr variant in the ATP13A2 gene among Chinesepatients with Parkinsonrsquos diseaserdquo Journal of Clinical Neuro-science vol 20 no 5 pp 761ndash762 2013
[28] H Darvish A Movafagh M D Omrani et al ldquoDetectionof copy number changes in genes associated with Parkinsonrsquosdisease in Iranian patientsrdquo Neuroscience Letters vol 551 pp75ndash78 2013
[29] C Vilarino-Guell A I Soto S J Lincoln et al ldquoATP13A2variability in Parkinson diseaserdquo Human Mutation vol 30 no3 pp 406ndash410 2009
[30] A Rakovic B Stiller A Djarmati et al ldquoGenetic associationstudy of the P-type ATPase ATP13A2 in late-onset ParkinsonrsquosdiseaserdquoMovement Disorders vol 24 no 3 pp 429ndash433 2009
[31] A S Najim Al-Din A Wriekat A Mubaidin M Dasoukiand M Hiari ldquoPallido-pyramidal degeneration supranuclearupgaze paresis and dementia Kufor-Rakeb syndromerdquo ActaNeurologica Scandinavica vol 89 no 5 pp 347ndash352 1994
[32] D R Williams A Hadeed A S Najim al-Din A Wreikatand A J Lees ldquoKufor Rakeb disease autosomal recessivelevodopa-responsive Parkinsonism with pyramidal degenera-tion supranuclear gaze palsy and dementiardquoMovement Disor-ders vol 20 no 10 pp 1264ndash1271 2005
[33] M I Behrens N Bruggemann P Chana et al ldquoClinicalspectrum of Kufor-Rakeb syndrome in the Chilean kindredwith ATP13A2 mutationsrdquoMovement Disorders vol 25 no 12pp 1929ndash1937 2010
[34] P J Schultheis T T Hagen K K OrsquoToole et al ldquoCharacteriza-tion of the P5 subfamily of P-type transport ATPases in micerdquoBiochemical and Biophysical Research Communications vol 323no 3 pp 731ndash738 2004
[35] B Schroder CWrocklage C Pan et al ldquoIntegral and associatedlysosomal membrane proteinsrdquo Traffic vol 8 no 12 pp 1676ndash1686 2007
[36] H Matsui F Sato S Sato et al ldquoATP13A2 deficiency inducesa decrease in cathepsin D activity fingerprint-like inclusionbody formation and selective degeneration of dopaminergicneuronsrdquo FEBS Letters vol 587 no 9 pp 1316ndash1325 2013
[37] B Dehay A Ramirez M Martinez-Vicente et al ldquoLoss of P-type ATPase ATP13A2PARK9 function induces general lyso-somal deficiency and leads to Parkinson disease neurodegen-erationrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 109 no 24 pp 9611ndash9616 2012
[38] K E Murphy L Cottle A M Gysbers A A Cooper and GM Halliday ldquoATP13A2 (PARK9) protein levels are reduced inbrain tissue of cases with Lewy bodiesrdquo Acta NeuropathologicaCommunications vol 1 article 11 2013
[39] G K Tofaris ldquoLysosome-dependent pathways as a unifyingtheme in Parkinsonrsquos diseaserdquo Movement Disorders vol 27 no11 pp 1364ndash1369 2012
[40] S M Kong B K Chan J S Park et al ldquoParkinsonrsquos disease-linked human PARK9 ATP13A2 maintains zinc homeosta-sis and promotes 120572-Synuclein externalization via exosomesrdquoHuman Molecular Genetics vol 23 no 11 pp 2816ndash2833 2014
[41] A D Gitler A Chesi M L Geddie et al ldquo120572-Synuclein ispart of a diverse and highly conserved interaction network that
includes PARK9 and manganese toxicityrdquo Nature Genetics vol41 no 3 pp 308ndash315 2009
[42] M Usenovic E Tresse J R Mazzulli J P Taylor and DKrainc ldquoDeficiency ofATP13A2 leads to lysosomal dysfunction120572-synuclein accumulation and neurotoxicityrdquo The Journal ofNeuroscience vol 32 no 12 pp 4240ndash4246 2012
[43] J S Park B Koentjoro D Veivers A Mackay-Sim and C MSue ldquoParkinsonrsquos disease-associated human ATP13A2 (PARK9)deficiency causes zinc dyshomeostasis andmitochondrial dys-functionrdquo Human Molecular Genetics vol 23 no 11 pp 2802ndash2815 2014
[44] A M Gusdon J Zhu B van Houten and C T ChuldquoATP13A2 regulates mitochondrial bioenergetics throughmacroautophagyrdquo Neurobiology of Disease vol 45 no 3 pp962ndash972 2012
[45] D Ramonet A Podhajska K Stafa et al ldquoPARK9-associatedATP13A2 localizes to intracellular acidic vesicles and regulatescation homeostasis and neuronal integrityrdquo Human MolecularGenetics vol 21 no 8 pp 1725ndash1743 2012
[46] R A Nixon D S Yang and J H Lee ldquoNeurodegenerativelysosomal disorders a continuum from development to lateagerdquo Autophagy vol 4 no 5 pp 590ndash599 2008
[47] B Dehay M Martinez-Vicente G A Caldwell et al ldquoLysoso-mal impairment in Parkinsonrsquos diseaserdquo Movement Disordersvol 28 no 6 pp 725ndash732 2013
[48] C W Olanow and P Brundin ldquoParkinsonrsquos disease and alphasynuclein is Parkinsonrsquos disease a prion-like disorderrdquo Move-ment Disorders vol 28 no 1 pp 31ndash40 2013
[49] J Bove M Martınez-Vicente and M Vila ldquoFighting neu-rodegeneration with rapamycin mechanistic insightsrdquo NatureReviews Neuroscience vol 12 no 8 pp 437ndash452 2011
[50] K Schmidt D M Wolfe B Stiller and D A Pearce ldquoCd2+Mn2+ Ni2+ and Se2+ toxicity to Saccharomyces cerevisiaelacking YPK9p the orthologue of human ATP13A2rdquo Biochem-ical and Biophysical Research Communications vol 383 no 2pp 198ndash202 2009
[51] P G Mastroberardino E K Hoffman M P Horowitz et al ldquoAnovel transferrinTfR2-mediated mitochondrial iron transportsystem is disrupted in Parkinsonrsquos diseaserdquo Neurobiology ofDisease vol 34 no 3 pp 417ndash431 2009
[52] C T Sheline J Zhu W Zhang C Shi and A Cai ldquoMitochon-drial inhibitor models of Huntingtonrsquos disease and Parkinsonrsquosdisease induce zinc accumulation and are attenuated by inhibi-tion of zinc neurotoxicity in vitro or in vivordquoNeurodegenerativeDiseases vol 11 no 1 pp 49ndash58 2013
[53] T Fukushima X Tan Y Luo and H Kanda ldquoSerum vitaminsand heavy metals in blood and urine and the correlationsamong them in parkinsonrsquos disease patients inChinardquoNeuroepi-demiology vol 36 no 4 pp 240ndash244 2011
[54] I Hozumi T Hasegawa A Honda et al ldquoPatterns of levelsof biological metals in CSF differ among neurodegenerativediseasesrdquo Journal of the Neurological Sciences vol 303 no 1-2pp 95ndash99 2011
[55] F J Jimenez-Jimenez P Fernandez-Calle M Martınez-Vanaclocha et al ldquoSerum levels of zinc and copper in patientswith Parkinsonrsquos diseaserdquo Journal of the Neurological Sciencesvol 112 no 1-2 pp 30ndash33 1992
[56] T R Guilarte ldquoManganese and Parkinsonrsquos disease a criticalreview and new findingsrdquo Environmental Health Perspectivesvol 118 no 8 pp 1071ndash1080 2010
BioMed Research International 9
[57] P Pals B van Everbroeck B Grubben et al ldquoCase-controlstudy of environmental risk factors for Parkinsonrsquos disease inBelgiumrdquo European Journal of Epidemiology vol 18 no 12 pp1133ndash1142 2003
[58] G Rentschler L Covolo A Ahmadi Haddad R G LucchiniS Zoni and K Broberg ldquoATP13A2 (PARK9) polymorphismsinfluence the neurotoxic effects of manganeserdquo NeuroToxicol-ogy vol 33 no 4 pp 697ndash702 2012
[59] J Tan T Zhang L Jiang et al ldquoRegulation of intracellularmanganese homeostasis by Kufor-Rakeb syndrome-associatedATP13A2 proteinrdquo Journal of Biological Chemistry vol 286 no34 pp 29654ndash29662 2011
[60] D Berg andHHochstrasser ldquoIronmetabolism in parkinsoniansyndromesrdquo Movement Disorders vol 21 no 9 pp 1299ndash13102006
[61] A E Oakley J F Collingwood J Dobson et al ldquoIndividualdopaminergic neurons show raised iron levels in Parkinsondiseaserdquo Neurology vol 68 no 21 pp 1820ndash1825 2007
[62] D Devos C Moreau and J C Devedjian ldquoTargeting chelatableiron as a therapeutic modality in Parkinsonrsquos diseaserdquo Antioxi-dants and Redox Signaling vol 21 no 2 pp 195ndash210 2014
[63] M Poli M Derosas S Luscieti et al ldquoPantothenate kinase-2 (Pank2) silencing causes cell growth reduction cell-specificferroportin upregulation and iron deregulationrdquo Neurobiologyof Disease vol 39 no 2 pp 204ndash210 2010
[64] T Tsunemi and D Krainc ldquoZn2+ dyshomeostasis caused by lossof ATP13A2PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulationrdquo Human Molecular Genetics vol 23no 11 pp 2791ndash2801 2014
[65] J Xu E Marzetti A Y Seo J Kim T A Prolla and CLeeuwenburgh ldquoThe emerging role of iron dyshomeostasis inthe mitochondrial decay of agingrdquo Mechanisms of Ageing andDevelopment vol 131 no 7-8 pp 487ndash493 2010
[66] M B H Youdim and P Riederer ldquoThe role of iron in senescenceof dopaminergic neurons in Parkinsonrsquos diseaserdquo Journal ofNeural Transmission Supplement no 40 pp 57ndash67 1993
[67] P Karki E Lee and M Aschner ldquoManganese neurotoxicity afocus on glutamate transportersrdquo Annals of Occupational andEnvironmental Medicine vol 25 no 1 article 4 2013
[68] H H Goebel L Gerhard E Kominami and M Hal-tia ldquoNeuronal ceroid-lipofuscinosismdashlate-infantile or Jansky-Bielschowsky typemdashrevisitedrdquo Brain Pathology vol 6 no 3 pp225ndash228 1996
[69] A Wohlke U Philipp P Bock et al ldquoA one base pair deletionin the canine ATP13A2 gene causes exon skipping and late-onset neuronal ceroid lipofuscinosis in the Tibetan terrierrdquoPLoS Genetics vol 7 no 10 Article ID e1002304 2011
[70] F H G Farias R Zeng G S Johnson et al ldquoA truncatingmuta-tion in ATP13A2 is responsible for adult-onset neuronal ceroidlipofuscinosis in Tibetan terriersrdquo Neurobiology of Disease vol42 no 3 pp 468ndash474 2011
[71] P J Schultheis S M Fleming A K Clippinger et al ldquoAtp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis limited120572-synuclein accumulation and age-dependent sensorimotordeficitsrdquo Human Molecular Genetics vol 22 no 10 pp 2067ndash2082 2013
[72] J G Burneo T Arnold C A Palmer R I Kuzniecky SJ Oh and E Faught ldquoAdult-onset neuronal ceroid lipofusci-nosis (Kufs disease) with autosomal dominant inheritance inAlabamardquo Epilepsia vol 44 no 6 pp 841ndash846 2003
[73] S F Berkovic S Carpenter F Andermann E Andermann andL S Wolfe ldquoKufsrsquo disease a critical reappraisalrdquo Brain vol 111no 1 part 1 pp 27ndash62 1988
[74] P C G Nijssen E Brusse A C M Leyten J J Martin JL J M Teepen and R A C Roos ldquoAutosomal dominantadult neuronal ceroid lipofuscinosis parkinsonism due to bothstriatal and nigral dysfunctionrdquoMovement Disorders vol 17 no3 pp 482ndash487 2002
[75] P E M Taschner N de Vos A D Thompson et al ldquoChro-mosome 16 microdeletion in a patient with juvenile neuronalceroid lipofuscinosis (Batten disease)rdquoThe American Journal ofHuman Genetics vol 56 no 3 pp 663ndash668 1995
[76] A Y Lavrov E S Ilyna E Y Zakharova A M Boukina andS V Tishkanina ldquoThe first three Russian cases of classical late-infantile neuronal ceroid lipofuscinosisrdquo European Journal ofPaediatric Neurology vol 6 no 3 pp 161ndash164 2002
[77] J Bras A Singleton M R Cookson and J Hardy ldquoEmerg-ing pathways in genetic Parkinsonrsquos disease potential role ofceramide metabolism in Lewy body diseaserdquo FEBS Journal vol275 no 23 pp 5767ndash5773 2008
[78] S El Haddad M Khoury M Daoud et al ldquoCLN5 and CLN8protein association with ceramide synthase biochemical andproteomic approachesrdquoElectrophoresis vol 33 no 24 pp 3798ndash3809 2012
[79] D Persaud-Sawin T Mousallem C Wang A Zucker E Kom-inami and R N Boustany ldquoNeuronal ceroid lipofuscinosis acommon pathwayrdquo Pediatric Research vol 61 no 2 pp 146ndash152 2007
[80] T J van Ham K L Thijssen R Breitling R M W Hofstra RH A Plasterk and E A A Nollen ldquoC elegansmodel identifiesgenetic modifiers of 120572-synuclein inclusion formation duringagingrdquo PLoS Genetics vol 4 no 3 Article ID e1000027 2008
[81] A Halperin D Elstein and A Zimran ldquoIncreased incidenceof Parkinson disease among relatives of patients with Gaucherdiseaserdquo Blood Cells Molecules and Diseases vol 36 no 3 pp426ndash428 2006
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
International Journal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
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Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Neural Plasticity
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Parkinsonrsquos Disease
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Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Psychiatry Journal
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Computational and Mathematical Methods in Medicine
Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International 5
ATP13A2 ProteaseX
CD63120572-Synuclein
Exosome
Degradation
LysosomeX XXXX
XXXXX
XXXX
MVBsAutophagosome
Intracellular
Externalisation
Extracellular
(a)
ATP13A2++ ATP13A2minusminus
ATP ATP
Degeneration
Mitochondria
ATPATP
Ca2+
ROS
(b)
Figure 1 Model of how ATP13A2 expression may affect lysosomes and mitochondria to prevent neurodegeneration (a) After 120572-synucleinhas been internalized by autophagosomes it can be immediately degraded in lysosomes containing ATP13A2 or secreted out of the cell viamultivesicular bodies (MVBs) also containing ATP13A2 Both routes prevent intracellular accumulation of 120572-synuclein (b) Knocking outATP13A2 expression in neurons leads to mitochondrial defects resulting in higher intracellular levels of reactive oxygen species (ROS) andCa2+ both of which contribute to neurodegeneration
ATP13A2 interacts preferentially with 120572-synuclein consistentwith a recent study showing that ATP13A2 colocalized with120572-synuclein in Lewy bodies but not with 120573-amyloid [38]
In addition to ensuring proper lysosomal functionATP13A2 may work in mitochondria such that the reducedactivity of ATP13A2 mutants may lead to mitochondrialdefects that contribute to neurodegeneration (Figure 1(b))[43] Fibroblasts from patients with KRS showed lowermitochondrial membrane potential and ATP synthesis ratesthan fibroblasts from healthy individuals [33] Cell culturesdeficient in ATP13A2 showed lower levels of autophagythan healthy cells leading to higher levels of reactiveoxygen species and concomitant oxidative stress [44]
Overexpressing ATP13A2 in neurons inhibited cadmium-induced mitochondrial fragmentation while silencingATP13A2 expression induced mitochondrial fragmentation[45] (Figure 1(b)) That same study further showed thatincreasing or decreasing ATP13A2 expression substantiallyshortened the neurites of primary midbrain DA neuronswithout affecting neurites of cortical neurons This maymean that the morphological and functional integrity of DAneurons depends on well-controlled ATP13A2 expression[45]
The available evidence suggests that ATP13A2 by sup-porting lysosomal andmitochondrial function helps preventthe 120572-synuclein aggregation associated with Parkinsonism
6 BioMed Research International
[46ndash49] The implication is that the ATP13A2 mutationslinked to KRS and other forms of PD are loss-of-functionmutations that reduce ATP13A2 activity sufficiently to induceneurodegeneration Future studies should examine in detailthe activity localization and binding partners of thesemutant proteins
42 ATP13A2 and Cation Accumulation ATP13A2 plays acritical role in the transmembrane transport of manganeseand zinc and perhaps of iron and cadmium as well [15]abnormal accumulation of any of these cations can causeneurodegeneration [41 50ndash52] Thus patients with PD havebeen reported to show elevated levels of manganese and zincin serum and cerebrospinal fluid [53ndash55] andmanganese andzinc exposure are significant environmental risk factors forPD [56 57] ATP13A2 helps protect cells from this toxicity byregulating the homeostasis ofmanganese and zinc in neurons[41 44 58 59] It may be that dysregulation of ATP13A2expression disrupts the homeostasis of manganese and zincin the brain leading to neurodegeneration
This possibility is consistent with the interpretation of theabnormal hypointensity in the putamina and caudate nucleiof patients with KRS in T2lowast diffuse MRI images as irondeposits (see Section 3) This finding led those authors topropose KRS with iron deposits as a distinct condition calledneurodegeneration with brain iron accumulation (NBIA)[20] Indeed iron accumulation was reported in the substan-tia nigra of PD patients [60] where it was particularly abun-dant in DA neurons [61] Administering the iron chelatordeferiprone to an animal model of PD induced by oxidativestress improved motor function and increased dopaminelevels in the striatum [62] In a pilot randomized clinical trialdouble-blind and placebo-controlled deferiprone showedsome ability to delay or reverse the progression of PD [62]
How mutations in ATP13A2may affect cation depositionis unclear We speculate that loss-of-function mutations inATP13A2 may work similarly to silencing of the PANK2gene which disrupts normal cation transfer and leads tomitochondrial and lysosomal dysfunction and ultimatelyto cation accumulation in the brain [63 64] In this wayATP13A2mutants may trigger deposition of the cations zincmanganese and iron leading to metal-induced oxidativedamage and ultimately causing decreases in glutathione per-oxidase activity glutathione (GSH) levels andmitochondrialComplex I activity as well as increases in levels of basal lipidperoxidation free radicals and glutamate [65ndash67] The netresult is significant neuronal loss that is the distinguishingpathological feature of PD
This proposed mechanism implies that regulating orrestoring the homeostasis of neurotoxic cations may be aneuroprotective therapy for patients with PD However onlytwo of the 37 PD patients with ATP13A2 mutations that wereviewed showed cation accumulation on T2lowast diffuse MRIimages (Table 2) and direct postmortem pathological evi-dence for metal accumulation in PD is lacking [20 33] Fur-ther studies are urgently needed to clarify whether ATP13A2mutations contribute to PD by increasing susceptibility tocation toxicity
5 ATP13A2 Mutations A Link betweenParkinsonism and NCLs
ATP13A2mutations have been identified not only in patientswith Parkinsonism but also in patients with neuronal ceroidlipofuscinoses (NCLs) [10] NCLs are a group of neurode-generative disorders that are also lysosomal storage diseasesClinical manifestations are seizures progressive cognitiveand motor decline and failing vision The pathologicalhallmark of NCLs is accumulation of autofluorescent lipopig-ment within neuronal lysosomes [68]
Recently the mutation c2429CgtG in exon 22 ofATP13A2 predicted to result in the amino acid substitutionpMet810Arg was identified in a Belgian family withNCLs [10] Affected individuals showed not only typicalNCL symptoms but also extrapyramidal involvementPostmortem pathological examination revealed extensivelipofuscin deposits in the cortex basal nuclei cerebellumand retinamdashbut not the white mattermdashand electronmicroscopy showed whorled lamellar inclusions typical ofNCLs [10] A link between ATP13A2 mutations and NCLpathogenesis is further supported by studies in animalmodels [69 70] In fact mice deficient in ATP13A2 exhibitedneuronal ceroid lipofuscinosis 120572-synuclein accumulationand age-dependent sensorimotor deficits suggesting that PDand NCLs share a pathogenic mechanism [71]
A shared disease pathwaymay help explain earlier reportsof individuals who demonstrate an ldquooverlappingrdquo neurode-generative syndrome combining Parkinsonism and NCLs[72ndash76] ATP13A2 is a lysosomal transport protein that helpsmaintain optimal pH in lysosomes [46] and ceramide ismetabolized in lysosomes [77] The apoptosis that appears tocause NCLs is associated with increased levels of ceramide[78 79] which have also been linked to 120572-synuclein deposi-tion whichmay contribute to PDpathogenesis [80] Itmay bethat ATP13A2 helps regulate ceramide metabolism such thatsignificant changes in ATP13A2 activitymay contribute to thepathogenesis of both PD and NCLs This model is similar tothat of the lysosomal storage disorder called Gaucher diseaseThe homozygousmutations in the 120573-glucocerebrosidase genethat cause Gaucher disease also increase risk of PD [81]Both diseases arise because lysosomal dysfunction leadsto excessive aggregation of substrates that normally aredegraded Analogously lysosomal dysfunction may underliethe clinically different neurodegenerative disorders of PD andNCLs
6 Summary
Much has been learned about the physiological functionsof ATP13A2 since mutations in the ATP13A2 gene werefirst linked to autosomal recessive familial KRS [7] Patientswith such mutations show onset at earlier ages than patientswith other forms of PD as well as some atypical clinicalsymptoms such as pyramidal degeneration supranuclearpalsy cognitive impairment and dystonia Studies in animalmodels of PD and in cultures of cells taken from patients withKRS and other types of PD suggest that ATP13A2 is important
BioMed Research International 7
for proper functioning of lysosomes and mitochondria andperhaps for clearance of divalent metals defects in any ofthese three processes are tightly associated with neurodegen-eration Nevertheless more studies are needed that directlyexamine how PD-associated mutations in ATP13A2 affectthe activity and localization of the protein and ultimatelythe integrity of these three processes ATP13A2 mutationsthat affect one of these processes lysosomal functioningmay simultaneously increase the risk of PD and NCLs Inotherwords these quite clinically different diseasesmay sharea mechanism of lysosomal dysfunction If further studiesvalidate the literature the ATP13A2 gene andor protein maybecome a suitable therapeutic target for treating both PD andNCLs
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Work by the authors related to this review was supportedby the Sichuan Key Project of Science and Technology (no2010SZ0086) and the National Natural Science Foundationof China (no 30700243)
References
[1] S Lesage and A Brice ldquoParkinsonrsquos disease from monogenicforms to genetic susceptibility factorsrdquo Human MolecularGenetics vol 18 no R1 pp R48ndashR59 2009
[2] V Bonifati ldquoGenetics of Parkinsonrsquos diseasemdashstate of the artrdquoParkinsonism amp Related Disorders vol 20 supplement 1 ppS23ndashS28 2014
[3] F Coppede ldquoGenetics and epigenetics of Parkinsonrsquos diseaserdquoScientific World Journal vol 2012 Article ID 489830 12 pages2012
[4] S Lesage E Lohmann F Tison F Durif A Durr and ABrice ldquoGene symbol PARK2 Disease parkinsonism juvenileautosomal recessiverdquoHuman genetics vol 123 no 1 article 1142008
[5] V Bonifati P Rizzu M J Van Baren et al ldquoMutations inthe DJ-1 gene associated with autosomal recessive early-onsetparkinsonismrdquo Science vol 299 no 5604 pp 256ndash259 2003
[6] Y Li H Tomiyama K Sato et al ldquoClinicogenetic study ofPINK1mutations in autosomal recessive early-onset parkinson-ismrdquo Neurology vol 64 no 11 pp 1955ndash1957 2005
[7] A Ramirez A Heimbach J Grundemann et al ldquoHeredi-tary parkinsonism with dementia is caused by mutations inATP13A2 encoding a lysosomal type 5 P-type ATPaserdquo NatureGenetics vol 38 no 10 pp 1184ndash1191 2006
[8] H Tomiyama H Yoshino K Ogaki et al ldquoPLA2G6 variant inParkinsons diseaserdquo Journal of Human Genetics vol 56 no 5pp 401ndash403 2011
[9] A Di Fonzo M C J Dekker P Montagna et al ldquoFBXO7mutations cause autosomal recessive early-onset parkinsonian-pyramidal syndromerdquo Neurology vol 72 no 3 pp 240ndash2452009
[10] J Bras A Verloes S A Schneider S E Mole and R J Guer-reiro ldquoMutation of the parkinsonism gene ATP13A2 causesneuronal ceroid-lipofuscinosisrdquo Human Molecular Geneticsvol 21 no 12 pp 2646ndash2650 2012
[11] A Di Fonzo H F Chien M Socal et al ldquoATP13A2 missensemutations in juvenile Parkinsonism and young onset Parkinsondiseaserdquo Neurology vol 68 no 19 pp 1557ndash1562 2007
[12] Y P Ning K Kanai H Tomiyama et al ldquoPARK9-linkedparkinsonism in eastern Asia mutation detection in ATP13A2and clinical phenotyperdquo Neurology vol 70 no 16 part 2 pp1491ndash1493 2008
[13] M Funayama H Tomiyama R M Wu et al ldquoRapid screeningof ATP13A2 variant with highresolution melting analysisrdquoMovement Disorders vol 25 no 14 pp 2434ndash2437 2010
[14] C H Lin E K Tan M L Chen et al ldquoNovel ATP13A2 variantassociated with Parkinson disease in Taiwan and SingaporerdquoNeurology vol 71 no 21 pp 1727ndash1732 2008
[15] C-M Chen C-H Lin H-F Juan et al ldquoATP13A2 variabilityin Taiwanese Parkinsonrsquos diseaserdquo American Journal of MedicalGenetics B Neuropsychiatric Genetics vol 156 no 6 pp 720ndash729 2011
[16] J Park PMehta A A Cooper et al ldquoPathogenic effects of novelmutations in the P-type ATPase ATP13A2 (PARK9) causingKufor-Rakeb syndrome a form of early-onset parkinsonismrdquoHuman Mutation vol 32 no 8 pp 956ndash964 2011
[17] L H Zhu X G Luo Y S Zhou et al ldquoLack of associationbetween three single nucleotide polymorphisms in the PARK9PARK15 and BST1 genes and Parkinsonrsquos disease in the north-ern Han Chinese populationrdquo Chinese Medical Journal vol 125no 4 pp 588ndash592 2012
[18] A Djarmati J Hagenah K Reetz et al ldquoATP13A2 variants inearly-onset Parkinsonrsquos disease patients and controlsrdquo Move-ment Disorders vol 24 no 14 pp 2104ndash2111 2009
[19] M Malakouti-Nejad G A Shahidi M Rohani et al ldquoIdenti-fication of pGln858lowast in ATP13A2 in two EOPD patients andpresentation of their clinical featuresrdquoNeuroscience Letters vol577 pp 106ndash111 2014
[20] S A Schneider C Paisan-Ruiz N P Quinn et al ldquoATP13A2mutations (PARK9) cause neurodegeneration with brain ironaccumulationrdquoMovement Disorders vol 25 no 8 pp 979ndash9842010
[21] C Y Fong A Rolfs T Schwarzbraun C Klein and F J KOrsquoCallaghan ldquoJuvenile parkinsonism associated with heterozy-gous frameshift ATP13A2 gene mutationrdquo European Journal ofPaediatric Neurology vol 15 no 3 pp 271ndash275 2011
[22] D Crosiers B Ceulemans B Meeus et al ldquoJuvenile dystonia-parkinsonism and dementia caused by a novel ATP13A2frameshift mutationrdquo Parkinsonism and Related Disorders vol17 no 2 pp 135ndash138 2011
[23] H Eiberg L Hansen L Korbo et al ldquoNovel mutation inATP13A2 widens the spectrum of Kufor-Rakeb syndrome(PARK9)rdquo Clinical Genetics vol 82 no 3 pp 256ndash263 2012
[24] L Santoro G J Breedveld F Manganelli et al ldquoNovelATP13A2(PARK9) homozygous mutation in a family with markedphenotype variabilityrdquo Neurogenetics vol 12 no 1 pp 33ndash392011
[25] Q Z Fei L Cao Q Xiao et al ldquoLack of association betweenATP13A2 Ala746Thr variant and Parkinsons disease in Hanpopulation of mainland Chinardquo Neuroscience Letters vol 475no 2 pp 61ndash63 2010
8 BioMed Research International
[26] X Y Mao J M Burgunder Z J Zhang et al ldquoATP13A2G2236A variant is rare in patients with early-onset Parkinsonrsquosdisease and familial Parkinsonrsquos disease from mainland ChinardquoParkinsonism and Related Disorders vol 16 no 3 pp 235ndash2362010
[27] A Y Y Chan L Baum N L S Tang et al ldquoThe role ofthe Ala746Thr variant in the ATP13A2 gene among Chinesepatients with Parkinsonrsquos diseaserdquo Journal of Clinical Neuro-science vol 20 no 5 pp 761ndash762 2013
[28] H Darvish A Movafagh M D Omrani et al ldquoDetectionof copy number changes in genes associated with Parkinsonrsquosdisease in Iranian patientsrdquo Neuroscience Letters vol 551 pp75ndash78 2013
[29] C Vilarino-Guell A I Soto S J Lincoln et al ldquoATP13A2variability in Parkinson diseaserdquo Human Mutation vol 30 no3 pp 406ndash410 2009
[30] A Rakovic B Stiller A Djarmati et al ldquoGenetic associationstudy of the P-type ATPase ATP13A2 in late-onset ParkinsonrsquosdiseaserdquoMovement Disorders vol 24 no 3 pp 429ndash433 2009
[31] A S Najim Al-Din A Wriekat A Mubaidin M Dasoukiand M Hiari ldquoPallido-pyramidal degeneration supranuclearupgaze paresis and dementia Kufor-Rakeb syndromerdquo ActaNeurologica Scandinavica vol 89 no 5 pp 347ndash352 1994
[32] D R Williams A Hadeed A S Najim al-Din A Wreikatand A J Lees ldquoKufor Rakeb disease autosomal recessivelevodopa-responsive Parkinsonism with pyramidal degenera-tion supranuclear gaze palsy and dementiardquoMovement Disor-ders vol 20 no 10 pp 1264ndash1271 2005
[33] M I Behrens N Bruggemann P Chana et al ldquoClinicalspectrum of Kufor-Rakeb syndrome in the Chilean kindredwith ATP13A2 mutationsrdquoMovement Disorders vol 25 no 12pp 1929ndash1937 2010
[34] P J Schultheis T T Hagen K K OrsquoToole et al ldquoCharacteriza-tion of the P5 subfamily of P-type transport ATPases in micerdquoBiochemical and Biophysical Research Communications vol 323no 3 pp 731ndash738 2004
[35] B Schroder CWrocklage C Pan et al ldquoIntegral and associatedlysosomal membrane proteinsrdquo Traffic vol 8 no 12 pp 1676ndash1686 2007
[36] H Matsui F Sato S Sato et al ldquoATP13A2 deficiency inducesa decrease in cathepsin D activity fingerprint-like inclusionbody formation and selective degeneration of dopaminergicneuronsrdquo FEBS Letters vol 587 no 9 pp 1316ndash1325 2013
[37] B Dehay A Ramirez M Martinez-Vicente et al ldquoLoss of P-type ATPase ATP13A2PARK9 function induces general lyso-somal deficiency and leads to Parkinson disease neurodegen-erationrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 109 no 24 pp 9611ndash9616 2012
[38] K E Murphy L Cottle A M Gysbers A A Cooper and GM Halliday ldquoATP13A2 (PARK9) protein levels are reduced inbrain tissue of cases with Lewy bodiesrdquo Acta NeuropathologicaCommunications vol 1 article 11 2013
[39] G K Tofaris ldquoLysosome-dependent pathways as a unifyingtheme in Parkinsonrsquos diseaserdquo Movement Disorders vol 27 no11 pp 1364ndash1369 2012
[40] S M Kong B K Chan J S Park et al ldquoParkinsonrsquos disease-linked human PARK9 ATP13A2 maintains zinc homeosta-sis and promotes 120572-Synuclein externalization via exosomesrdquoHuman Molecular Genetics vol 23 no 11 pp 2816ndash2833 2014
[41] A D Gitler A Chesi M L Geddie et al ldquo120572-Synuclein ispart of a diverse and highly conserved interaction network that
includes PARK9 and manganese toxicityrdquo Nature Genetics vol41 no 3 pp 308ndash315 2009
[42] M Usenovic E Tresse J R Mazzulli J P Taylor and DKrainc ldquoDeficiency ofATP13A2 leads to lysosomal dysfunction120572-synuclein accumulation and neurotoxicityrdquo The Journal ofNeuroscience vol 32 no 12 pp 4240ndash4246 2012
[43] J S Park B Koentjoro D Veivers A Mackay-Sim and C MSue ldquoParkinsonrsquos disease-associated human ATP13A2 (PARK9)deficiency causes zinc dyshomeostasis andmitochondrial dys-functionrdquo Human Molecular Genetics vol 23 no 11 pp 2802ndash2815 2014
[44] A M Gusdon J Zhu B van Houten and C T ChuldquoATP13A2 regulates mitochondrial bioenergetics throughmacroautophagyrdquo Neurobiology of Disease vol 45 no 3 pp962ndash972 2012
[45] D Ramonet A Podhajska K Stafa et al ldquoPARK9-associatedATP13A2 localizes to intracellular acidic vesicles and regulatescation homeostasis and neuronal integrityrdquo Human MolecularGenetics vol 21 no 8 pp 1725ndash1743 2012
[46] R A Nixon D S Yang and J H Lee ldquoNeurodegenerativelysosomal disorders a continuum from development to lateagerdquo Autophagy vol 4 no 5 pp 590ndash599 2008
[47] B Dehay M Martinez-Vicente G A Caldwell et al ldquoLysoso-mal impairment in Parkinsonrsquos diseaserdquo Movement Disordersvol 28 no 6 pp 725ndash732 2013
[48] C W Olanow and P Brundin ldquoParkinsonrsquos disease and alphasynuclein is Parkinsonrsquos disease a prion-like disorderrdquo Move-ment Disorders vol 28 no 1 pp 31ndash40 2013
[49] J Bove M Martınez-Vicente and M Vila ldquoFighting neu-rodegeneration with rapamycin mechanistic insightsrdquo NatureReviews Neuroscience vol 12 no 8 pp 437ndash452 2011
[50] K Schmidt D M Wolfe B Stiller and D A Pearce ldquoCd2+Mn2+ Ni2+ and Se2+ toxicity to Saccharomyces cerevisiaelacking YPK9p the orthologue of human ATP13A2rdquo Biochem-ical and Biophysical Research Communications vol 383 no 2pp 198ndash202 2009
[51] P G Mastroberardino E K Hoffman M P Horowitz et al ldquoAnovel transferrinTfR2-mediated mitochondrial iron transportsystem is disrupted in Parkinsonrsquos diseaserdquo Neurobiology ofDisease vol 34 no 3 pp 417ndash431 2009
[52] C T Sheline J Zhu W Zhang C Shi and A Cai ldquoMitochon-drial inhibitor models of Huntingtonrsquos disease and Parkinsonrsquosdisease induce zinc accumulation and are attenuated by inhibi-tion of zinc neurotoxicity in vitro or in vivordquoNeurodegenerativeDiseases vol 11 no 1 pp 49ndash58 2013
[53] T Fukushima X Tan Y Luo and H Kanda ldquoSerum vitaminsand heavy metals in blood and urine and the correlationsamong them in parkinsonrsquos disease patients inChinardquoNeuroepi-demiology vol 36 no 4 pp 240ndash244 2011
[54] I Hozumi T Hasegawa A Honda et al ldquoPatterns of levelsof biological metals in CSF differ among neurodegenerativediseasesrdquo Journal of the Neurological Sciences vol 303 no 1-2pp 95ndash99 2011
[55] F J Jimenez-Jimenez P Fernandez-Calle M Martınez-Vanaclocha et al ldquoSerum levels of zinc and copper in patientswith Parkinsonrsquos diseaserdquo Journal of the Neurological Sciencesvol 112 no 1-2 pp 30ndash33 1992
[56] T R Guilarte ldquoManganese and Parkinsonrsquos disease a criticalreview and new findingsrdquo Environmental Health Perspectivesvol 118 no 8 pp 1071ndash1080 2010
BioMed Research International 9
[57] P Pals B van Everbroeck B Grubben et al ldquoCase-controlstudy of environmental risk factors for Parkinsonrsquos disease inBelgiumrdquo European Journal of Epidemiology vol 18 no 12 pp1133ndash1142 2003
[58] G Rentschler L Covolo A Ahmadi Haddad R G LucchiniS Zoni and K Broberg ldquoATP13A2 (PARK9) polymorphismsinfluence the neurotoxic effects of manganeserdquo NeuroToxicol-ogy vol 33 no 4 pp 697ndash702 2012
[59] J Tan T Zhang L Jiang et al ldquoRegulation of intracellularmanganese homeostasis by Kufor-Rakeb syndrome-associatedATP13A2 proteinrdquo Journal of Biological Chemistry vol 286 no34 pp 29654ndash29662 2011
[60] D Berg andHHochstrasser ldquoIronmetabolism in parkinsoniansyndromesrdquo Movement Disorders vol 21 no 9 pp 1299ndash13102006
[61] A E Oakley J F Collingwood J Dobson et al ldquoIndividualdopaminergic neurons show raised iron levels in Parkinsondiseaserdquo Neurology vol 68 no 21 pp 1820ndash1825 2007
[62] D Devos C Moreau and J C Devedjian ldquoTargeting chelatableiron as a therapeutic modality in Parkinsonrsquos diseaserdquo Antioxi-dants and Redox Signaling vol 21 no 2 pp 195ndash210 2014
[63] M Poli M Derosas S Luscieti et al ldquoPantothenate kinase-2 (Pank2) silencing causes cell growth reduction cell-specificferroportin upregulation and iron deregulationrdquo Neurobiologyof Disease vol 39 no 2 pp 204ndash210 2010
[64] T Tsunemi and D Krainc ldquoZn2+ dyshomeostasis caused by lossof ATP13A2PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulationrdquo Human Molecular Genetics vol 23no 11 pp 2791ndash2801 2014
[65] J Xu E Marzetti A Y Seo J Kim T A Prolla and CLeeuwenburgh ldquoThe emerging role of iron dyshomeostasis inthe mitochondrial decay of agingrdquo Mechanisms of Ageing andDevelopment vol 131 no 7-8 pp 487ndash493 2010
[66] M B H Youdim and P Riederer ldquoThe role of iron in senescenceof dopaminergic neurons in Parkinsonrsquos diseaserdquo Journal ofNeural Transmission Supplement no 40 pp 57ndash67 1993
[67] P Karki E Lee and M Aschner ldquoManganese neurotoxicity afocus on glutamate transportersrdquo Annals of Occupational andEnvironmental Medicine vol 25 no 1 article 4 2013
[68] H H Goebel L Gerhard E Kominami and M Hal-tia ldquoNeuronal ceroid-lipofuscinosismdashlate-infantile or Jansky-Bielschowsky typemdashrevisitedrdquo Brain Pathology vol 6 no 3 pp225ndash228 1996
[69] A Wohlke U Philipp P Bock et al ldquoA one base pair deletionin the canine ATP13A2 gene causes exon skipping and late-onset neuronal ceroid lipofuscinosis in the Tibetan terrierrdquoPLoS Genetics vol 7 no 10 Article ID e1002304 2011
[70] F H G Farias R Zeng G S Johnson et al ldquoA truncatingmuta-tion in ATP13A2 is responsible for adult-onset neuronal ceroidlipofuscinosis in Tibetan terriersrdquo Neurobiology of Disease vol42 no 3 pp 468ndash474 2011
[71] P J Schultheis S M Fleming A K Clippinger et al ldquoAtp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis limited120572-synuclein accumulation and age-dependent sensorimotordeficitsrdquo Human Molecular Genetics vol 22 no 10 pp 2067ndash2082 2013
[72] J G Burneo T Arnold C A Palmer R I Kuzniecky SJ Oh and E Faught ldquoAdult-onset neuronal ceroid lipofusci-nosis (Kufs disease) with autosomal dominant inheritance inAlabamardquo Epilepsia vol 44 no 6 pp 841ndash846 2003
[73] S F Berkovic S Carpenter F Andermann E Andermann andL S Wolfe ldquoKufsrsquo disease a critical reappraisalrdquo Brain vol 111no 1 part 1 pp 27ndash62 1988
[74] P C G Nijssen E Brusse A C M Leyten J J Martin JL J M Teepen and R A C Roos ldquoAutosomal dominantadult neuronal ceroid lipofuscinosis parkinsonism due to bothstriatal and nigral dysfunctionrdquoMovement Disorders vol 17 no3 pp 482ndash487 2002
[75] P E M Taschner N de Vos A D Thompson et al ldquoChro-mosome 16 microdeletion in a patient with juvenile neuronalceroid lipofuscinosis (Batten disease)rdquoThe American Journal ofHuman Genetics vol 56 no 3 pp 663ndash668 1995
[76] A Y Lavrov E S Ilyna E Y Zakharova A M Boukina andS V Tishkanina ldquoThe first three Russian cases of classical late-infantile neuronal ceroid lipofuscinosisrdquo European Journal ofPaediatric Neurology vol 6 no 3 pp 161ndash164 2002
[77] J Bras A Singleton M R Cookson and J Hardy ldquoEmerg-ing pathways in genetic Parkinsonrsquos disease potential role ofceramide metabolism in Lewy body diseaserdquo FEBS Journal vol275 no 23 pp 5767ndash5773 2008
[78] S El Haddad M Khoury M Daoud et al ldquoCLN5 and CLN8protein association with ceramide synthase biochemical andproteomic approachesrdquoElectrophoresis vol 33 no 24 pp 3798ndash3809 2012
[79] D Persaud-Sawin T Mousallem C Wang A Zucker E Kom-inami and R N Boustany ldquoNeuronal ceroid lipofuscinosis acommon pathwayrdquo Pediatric Research vol 61 no 2 pp 146ndash152 2007
[80] T J van Ham K L Thijssen R Breitling R M W Hofstra RH A Plasterk and E A A Nollen ldquoC elegansmodel identifiesgenetic modifiers of 120572-synuclein inclusion formation duringagingrdquo PLoS Genetics vol 4 no 3 Article ID e1000027 2008
[81] A Halperin D Elstein and A Zimran ldquoIncreased incidenceof Parkinson disease among relatives of patients with Gaucherdiseaserdquo Blood Cells Molecules and Diseases vol 36 no 3 pp426ndash428 2006
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
International Journal of
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neuroscience Journal
Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Psychiatry Journal
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Brain ScienceInternational Journal of
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neurodegenerative Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
6 BioMed Research International
[46ndash49] The implication is that the ATP13A2 mutationslinked to KRS and other forms of PD are loss-of-functionmutations that reduce ATP13A2 activity sufficiently to induceneurodegeneration Future studies should examine in detailthe activity localization and binding partners of thesemutant proteins
42 ATP13A2 and Cation Accumulation ATP13A2 plays acritical role in the transmembrane transport of manganeseand zinc and perhaps of iron and cadmium as well [15]abnormal accumulation of any of these cations can causeneurodegeneration [41 50ndash52] Thus patients with PD havebeen reported to show elevated levels of manganese and zincin serum and cerebrospinal fluid [53ndash55] andmanganese andzinc exposure are significant environmental risk factors forPD [56 57] ATP13A2 helps protect cells from this toxicity byregulating the homeostasis ofmanganese and zinc in neurons[41 44 58 59] It may be that dysregulation of ATP13A2expression disrupts the homeostasis of manganese and zincin the brain leading to neurodegeneration
This possibility is consistent with the interpretation of theabnormal hypointensity in the putamina and caudate nucleiof patients with KRS in T2lowast diffuse MRI images as irondeposits (see Section 3) This finding led those authors topropose KRS with iron deposits as a distinct condition calledneurodegeneration with brain iron accumulation (NBIA)[20] Indeed iron accumulation was reported in the substan-tia nigra of PD patients [60] where it was particularly abun-dant in DA neurons [61] Administering the iron chelatordeferiprone to an animal model of PD induced by oxidativestress improved motor function and increased dopaminelevels in the striatum [62] In a pilot randomized clinical trialdouble-blind and placebo-controlled deferiprone showedsome ability to delay or reverse the progression of PD [62]
How mutations in ATP13A2may affect cation depositionis unclear We speculate that loss-of-function mutations inATP13A2 may work similarly to silencing of the PANK2gene which disrupts normal cation transfer and leads tomitochondrial and lysosomal dysfunction and ultimatelyto cation accumulation in the brain [63 64] In this wayATP13A2mutants may trigger deposition of the cations zincmanganese and iron leading to metal-induced oxidativedamage and ultimately causing decreases in glutathione per-oxidase activity glutathione (GSH) levels andmitochondrialComplex I activity as well as increases in levels of basal lipidperoxidation free radicals and glutamate [65ndash67] The netresult is significant neuronal loss that is the distinguishingpathological feature of PD
This proposed mechanism implies that regulating orrestoring the homeostasis of neurotoxic cations may be aneuroprotective therapy for patients with PD However onlytwo of the 37 PD patients with ATP13A2 mutations that wereviewed showed cation accumulation on T2lowast diffuse MRIimages (Table 2) and direct postmortem pathological evi-dence for metal accumulation in PD is lacking [20 33] Fur-ther studies are urgently needed to clarify whether ATP13A2mutations contribute to PD by increasing susceptibility tocation toxicity
5 ATP13A2 Mutations A Link betweenParkinsonism and NCLs
ATP13A2mutations have been identified not only in patientswith Parkinsonism but also in patients with neuronal ceroidlipofuscinoses (NCLs) [10] NCLs are a group of neurode-generative disorders that are also lysosomal storage diseasesClinical manifestations are seizures progressive cognitiveand motor decline and failing vision The pathologicalhallmark of NCLs is accumulation of autofluorescent lipopig-ment within neuronal lysosomes [68]
Recently the mutation c2429CgtG in exon 22 ofATP13A2 predicted to result in the amino acid substitutionpMet810Arg was identified in a Belgian family withNCLs [10] Affected individuals showed not only typicalNCL symptoms but also extrapyramidal involvementPostmortem pathological examination revealed extensivelipofuscin deposits in the cortex basal nuclei cerebellumand retinamdashbut not the white mattermdashand electronmicroscopy showed whorled lamellar inclusions typical ofNCLs [10] A link between ATP13A2 mutations and NCLpathogenesis is further supported by studies in animalmodels [69 70] In fact mice deficient in ATP13A2 exhibitedneuronal ceroid lipofuscinosis 120572-synuclein accumulationand age-dependent sensorimotor deficits suggesting that PDand NCLs share a pathogenic mechanism [71]
A shared disease pathwaymay help explain earlier reportsof individuals who demonstrate an ldquooverlappingrdquo neurode-generative syndrome combining Parkinsonism and NCLs[72ndash76] ATP13A2 is a lysosomal transport protein that helpsmaintain optimal pH in lysosomes [46] and ceramide ismetabolized in lysosomes [77] The apoptosis that appears tocause NCLs is associated with increased levels of ceramide[78 79] which have also been linked to 120572-synuclein deposi-tion whichmay contribute to PDpathogenesis [80] Itmay bethat ATP13A2 helps regulate ceramide metabolism such thatsignificant changes in ATP13A2 activitymay contribute to thepathogenesis of both PD and NCLs This model is similar tothat of the lysosomal storage disorder called Gaucher diseaseThe homozygousmutations in the 120573-glucocerebrosidase genethat cause Gaucher disease also increase risk of PD [81]Both diseases arise because lysosomal dysfunction leadsto excessive aggregation of substrates that normally aredegraded Analogously lysosomal dysfunction may underliethe clinically different neurodegenerative disorders of PD andNCLs
6 Summary
Much has been learned about the physiological functionsof ATP13A2 since mutations in the ATP13A2 gene werefirst linked to autosomal recessive familial KRS [7] Patientswith such mutations show onset at earlier ages than patientswith other forms of PD as well as some atypical clinicalsymptoms such as pyramidal degeneration supranuclearpalsy cognitive impairment and dystonia Studies in animalmodels of PD and in cultures of cells taken from patients withKRS and other types of PD suggest that ATP13A2 is important
BioMed Research International 7
for proper functioning of lysosomes and mitochondria andperhaps for clearance of divalent metals defects in any ofthese three processes are tightly associated with neurodegen-eration Nevertheless more studies are needed that directlyexamine how PD-associated mutations in ATP13A2 affectthe activity and localization of the protein and ultimatelythe integrity of these three processes ATP13A2 mutationsthat affect one of these processes lysosomal functioningmay simultaneously increase the risk of PD and NCLs Inotherwords these quite clinically different diseasesmay sharea mechanism of lysosomal dysfunction If further studiesvalidate the literature the ATP13A2 gene andor protein maybecome a suitable therapeutic target for treating both PD andNCLs
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Work by the authors related to this review was supportedby the Sichuan Key Project of Science and Technology (no2010SZ0086) and the National Natural Science Foundationof China (no 30700243)
References
[1] S Lesage and A Brice ldquoParkinsonrsquos disease from monogenicforms to genetic susceptibility factorsrdquo Human MolecularGenetics vol 18 no R1 pp R48ndashR59 2009
[2] V Bonifati ldquoGenetics of Parkinsonrsquos diseasemdashstate of the artrdquoParkinsonism amp Related Disorders vol 20 supplement 1 ppS23ndashS28 2014
[3] F Coppede ldquoGenetics and epigenetics of Parkinsonrsquos diseaserdquoScientific World Journal vol 2012 Article ID 489830 12 pages2012
[4] S Lesage E Lohmann F Tison F Durif A Durr and ABrice ldquoGene symbol PARK2 Disease parkinsonism juvenileautosomal recessiverdquoHuman genetics vol 123 no 1 article 1142008
[5] V Bonifati P Rizzu M J Van Baren et al ldquoMutations inthe DJ-1 gene associated with autosomal recessive early-onsetparkinsonismrdquo Science vol 299 no 5604 pp 256ndash259 2003
[6] Y Li H Tomiyama K Sato et al ldquoClinicogenetic study ofPINK1mutations in autosomal recessive early-onset parkinson-ismrdquo Neurology vol 64 no 11 pp 1955ndash1957 2005
[7] A Ramirez A Heimbach J Grundemann et al ldquoHeredi-tary parkinsonism with dementia is caused by mutations inATP13A2 encoding a lysosomal type 5 P-type ATPaserdquo NatureGenetics vol 38 no 10 pp 1184ndash1191 2006
[8] H Tomiyama H Yoshino K Ogaki et al ldquoPLA2G6 variant inParkinsons diseaserdquo Journal of Human Genetics vol 56 no 5pp 401ndash403 2011
[9] A Di Fonzo M C J Dekker P Montagna et al ldquoFBXO7mutations cause autosomal recessive early-onset parkinsonian-pyramidal syndromerdquo Neurology vol 72 no 3 pp 240ndash2452009
[10] J Bras A Verloes S A Schneider S E Mole and R J Guer-reiro ldquoMutation of the parkinsonism gene ATP13A2 causesneuronal ceroid-lipofuscinosisrdquo Human Molecular Geneticsvol 21 no 12 pp 2646ndash2650 2012
[11] A Di Fonzo H F Chien M Socal et al ldquoATP13A2 missensemutations in juvenile Parkinsonism and young onset Parkinsondiseaserdquo Neurology vol 68 no 19 pp 1557ndash1562 2007
[12] Y P Ning K Kanai H Tomiyama et al ldquoPARK9-linkedparkinsonism in eastern Asia mutation detection in ATP13A2and clinical phenotyperdquo Neurology vol 70 no 16 part 2 pp1491ndash1493 2008
[13] M Funayama H Tomiyama R M Wu et al ldquoRapid screeningof ATP13A2 variant with highresolution melting analysisrdquoMovement Disorders vol 25 no 14 pp 2434ndash2437 2010
[14] C H Lin E K Tan M L Chen et al ldquoNovel ATP13A2 variantassociated with Parkinson disease in Taiwan and SingaporerdquoNeurology vol 71 no 21 pp 1727ndash1732 2008
[15] C-M Chen C-H Lin H-F Juan et al ldquoATP13A2 variabilityin Taiwanese Parkinsonrsquos diseaserdquo American Journal of MedicalGenetics B Neuropsychiatric Genetics vol 156 no 6 pp 720ndash729 2011
[16] J Park PMehta A A Cooper et al ldquoPathogenic effects of novelmutations in the P-type ATPase ATP13A2 (PARK9) causingKufor-Rakeb syndrome a form of early-onset parkinsonismrdquoHuman Mutation vol 32 no 8 pp 956ndash964 2011
[17] L H Zhu X G Luo Y S Zhou et al ldquoLack of associationbetween three single nucleotide polymorphisms in the PARK9PARK15 and BST1 genes and Parkinsonrsquos disease in the north-ern Han Chinese populationrdquo Chinese Medical Journal vol 125no 4 pp 588ndash592 2012
[18] A Djarmati J Hagenah K Reetz et al ldquoATP13A2 variants inearly-onset Parkinsonrsquos disease patients and controlsrdquo Move-ment Disorders vol 24 no 14 pp 2104ndash2111 2009
[19] M Malakouti-Nejad G A Shahidi M Rohani et al ldquoIdenti-fication of pGln858lowast in ATP13A2 in two EOPD patients andpresentation of their clinical featuresrdquoNeuroscience Letters vol577 pp 106ndash111 2014
[20] S A Schneider C Paisan-Ruiz N P Quinn et al ldquoATP13A2mutations (PARK9) cause neurodegeneration with brain ironaccumulationrdquoMovement Disorders vol 25 no 8 pp 979ndash9842010
[21] C Y Fong A Rolfs T Schwarzbraun C Klein and F J KOrsquoCallaghan ldquoJuvenile parkinsonism associated with heterozy-gous frameshift ATP13A2 gene mutationrdquo European Journal ofPaediatric Neurology vol 15 no 3 pp 271ndash275 2011
[22] D Crosiers B Ceulemans B Meeus et al ldquoJuvenile dystonia-parkinsonism and dementia caused by a novel ATP13A2frameshift mutationrdquo Parkinsonism and Related Disorders vol17 no 2 pp 135ndash138 2011
[23] H Eiberg L Hansen L Korbo et al ldquoNovel mutation inATP13A2 widens the spectrum of Kufor-Rakeb syndrome(PARK9)rdquo Clinical Genetics vol 82 no 3 pp 256ndash263 2012
[24] L Santoro G J Breedveld F Manganelli et al ldquoNovelATP13A2(PARK9) homozygous mutation in a family with markedphenotype variabilityrdquo Neurogenetics vol 12 no 1 pp 33ndash392011
[25] Q Z Fei L Cao Q Xiao et al ldquoLack of association betweenATP13A2 Ala746Thr variant and Parkinsons disease in Hanpopulation of mainland Chinardquo Neuroscience Letters vol 475no 2 pp 61ndash63 2010
8 BioMed Research International
[26] X Y Mao J M Burgunder Z J Zhang et al ldquoATP13A2G2236A variant is rare in patients with early-onset Parkinsonrsquosdisease and familial Parkinsonrsquos disease from mainland ChinardquoParkinsonism and Related Disorders vol 16 no 3 pp 235ndash2362010
[27] A Y Y Chan L Baum N L S Tang et al ldquoThe role ofthe Ala746Thr variant in the ATP13A2 gene among Chinesepatients with Parkinsonrsquos diseaserdquo Journal of Clinical Neuro-science vol 20 no 5 pp 761ndash762 2013
[28] H Darvish A Movafagh M D Omrani et al ldquoDetectionof copy number changes in genes associated with Parkinsonrsquosdisease in Iranian patientsrdquo Neuroscience Letters vol 551 pp75ndash78 2013
[29] C Vilarino-Guell A I Soto S J Lincoln et al ldquoATP13A2variability in Parkinson diseaserdquo Human Mutation vol 30 no3 pp 406ndash410 2009
[30] A Rakovic B Stiller A Djarmati et al ldquoGenetic associationstudy of the P-type ATPase ATP13A2 in late-onset ParkinsonrsquosdiseaserdquoMovement Disorders vol 24 no 3 pp 429ndash433 2009
[31] A S Najim Al-Din A Wriekat A Mubaidin M Dasoukiand M Hiari ldquoPallido-pyramidal degeneration supranuclearupgaze paresis and dementia Kufor-Rakeb syndromerdquo ActaNeurologica Scandinavica vol 89 no 5 pp 347ndash352 1994
[32] D R Williams A Hadeed A S Najim al-Din A Wreikatand A J Lees ldquoKufor Rakeb disease autosomal recessivelevodopa-responsive Parkinsonism with pyramidal degenera-tion supranuclear gaze palsy and dementiardquoMovement Disor-ders vol 20 no 10 pp 1264ndash1271 2005
[33] M I Behrens N Bruggemann P Chana et al ldquoClinicalspectrum of Kufor-Rakeb syndrome in the Chilean kindredwith ATP13A2 mutationsrdquoMovement Disorders vol 25 no 12pp 1929ndash1937 2010
[34] P J Schultheis T T Hagen K K OrsquoToole et al ldquoCharacteriza-tion of the P5 subfamily of P-type transport ATPases in micerdquoBiochemical and Biophysical Research Communications vol 323no 3 pp 731ndash738 2004
[35] B Schroder CWrocklage C Pan et al ldquoIntegral and associatedlysosomal membrane proteinsrdquo Traffic vol 8 no 12 pp 1676ndash1686 2007
[36] H Matsui F Sato S Sato et al ldquoATP13A2 deficiency inducesa decrease in cathepsin D activity fingerprint-like inclusionbody formation and selective degeneration of dopaminergicneuronsrdquo FEBS Letters vol 587 no 9 pp 1316ndash1325 2013
[37] B Dehay A Ramirez M Martinez-Vicente et al ldquoLoss of P-type ATPase ATP13A2PARK9 function induces general lyso-somal deficiency and leads to Parkinson disease neurodegen-erationrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 109 no 24 pp 9611ndash9616 2012
[38] K E Murphy L Cottle A M Gysbers A A Cooper and GM Halliday ldquoATP13A2 (PARK9) protein levels are reduced inbrain tissue of cases with Lewy bodiesrdquo Acta NeuropathologicaCommunications vol 1 article 11 2013
[39] G K Tofaris ldquoLysosome-dependent pathways as a unifyingtheme in Parkinsonrsquos diseaserdquo Movement Disorders vol 27 no11 pp 1364ndash1369 2012
[40] S M Kong B K Chan J S Park et al ldquoParkinsonrsquos disease-linked human PARK9 ATP13A2 maintains zinc homeosta-sis and promotes 120572-Synuclein externalization via exosomesrdquoHuman Molecular Genetics vol 23 no 11 pp 2816ndash2833 2014
[41] A D Gitler A Chesi M L Geddie et al ldquo120572-Synuclein ispart of a diverse and highly conserved interaction network that
includes PARK9 and manganese toxicityrdquo Nature Genetics vol41 no 3 pp 308ndash315 2009
[42] M Usenovic E Tresse J R Mazzulli J P Taylor and DKrainc ldquoDeficiency ofATP13A2 leads to lysosomal dysfunction120572-synuclein accumulation and neurotoxicityrdquo The Journal ofNeuroscience vol 32 no 12 pp 4240ndash4246 2012
[43] J S Park B Koentjoro D Veivers A Mackay-Sim and C MSue ldquoParkinsonrsquos disease-associated human ATP13A2 (PARK9)deficiency causes zinc dyshomeostasis andmitochondrial dys-functionrdquo Human Molecular Genetics vol 23 no 11 pp 2802ndash2815 2014
[44] A M Gusdon J Zhu B van Houten and C T ChuldquoATP13A2 regulates mitochondrial bioenergetics throughmacroautophagyrdquo Neurobiology of Disease vol 45 no 3 pp962ndash972 2012
[45] D Ramonet A Podhajska K Stafa et al ldquoPARK9-associatedATP13A2 localizes to intracellular acidic vesicles and regulatescation homeostasis and neuronal integrityrdquo Human MolecularGenetics vol 21 no 8 pp 1725ndash1743 2012
[46] R A Nixon D S Yang and J H Lee ldquoNeurodegenerativelysosomal disorders a continuum from development to lateagerdquo Autophagy vol 4 no 5 pp 590ndash599 2008
[47] B Dehay M Martinez-Vicente G A Caldwell et al ldquoLysoso-mal impairment in Parkinsonrsquos diseaserdquo Movement Disordersvol 28 no 6 pp 725ndash732 2013
[48] C W Olanow and P Brundin ldquoParkinsonrsquos disease and alphasynuclein is Parkinsonrsquos disease a prion-like disorderrdquo Move-ment Disorders vol 28 no 1 pp 31ndash40 2013
[49] J Bove M Martınez-Vicente and M Vila ldquoFighting neu-rodegeneration with rapamycin mechanistic insightsrdquo NatureReviews Neuroscience vol 12 no 8 pp 437ndash452 2011
[50] K Schmidt D M Wolfe B Stiller and D A Pearce ldquoCd2+Mn2+ Ni2+ and Se2+ toxicity to Saccharomyces cerevisiaelacking YPK9p the orthologue of human ATP13A2rdquo Biochem-ical and Biophysical Research Communications vol 383 no 2pp 198ndash202 2009
[51] P G Mastroberardino E K Hoffman M P Horowitz et al ldquoAnovel transferrinTfR2-mediated mitochondrial iron transportsystem is disrupted in Parkinsonrsquos diseaserdquo Neurobiology ofDisease vol 34 no 3 pp 417ndash431 2009
[52] C T Sheline J Zhu W Zhang C Shi and A Cai ldquoMitochon-drial inhibitor models of Huntingtonrsquos disease and Parkinsonrsquosdisease induce zinc accumulation and are attenuated by inhibi-tion of zinc neurotoxicity in vitro or in vivordquoNeurodegenerativeDiseases vol 11 no 1 pp 49ndash58 2013
[53] T Fukushima X Tan Y Luo and H Kanda ldquoSerum vitaminsand heavy metals in blood and urine and the correlationsamong them in parkinsonrsquos disease patients inChinardquoNeuroepi-demiology vol 36 no 4 pp 240ndash244 2011
[54] I Hozumi T Hasegawa A Honda et al ldquoPatterns of levelsof biological metals in CSF differ among neurodegenerativediseasesrdquo Journal of the Neurological Sciences vol 303 no 1-2pp 95ndash99 2011
[55] F J Jimenez-Jimenez P Fernandez-Calle M Martınez-Vanaclocha et al ldquoSerum levels of zinc and copper in patientswith Parkinsonrsquos diseaserdquo Journal of the Neurological Sciencesvol 112 no 1-2 pp 30ndash33 1992
[56] T R Guilarte ldquoManganese and Parkinsonrsquos disease a criticalreview and new findingsrdquo Environmental Health Perspectivesvol 118 no 8 pp 1071ndash1080 2010
BioMed Research International 9
[57] P Pals B van Everbroeck B Grubben et al ldquoCase-controlstudy of environmental risk factors for Parkinsonrsquos disease inBelgiumrdquo European Journal of Epidemiology vol 18 no 12 pp1133ndash1142 2003
[58] G Rentschler L Covolo A Ahmadi Haddad R G LucchiniS Zoni and K Broberg ldquoATP13A2 (PARK9) polymorphismsinfluence the neurotoxic effects of manganeserdquo NeuroToxicol-ogy vol 33 no 4 pp 697ndash702 2012
[59] J Tan T Zhang L Jiang et al ldquoRegulation of intracellularmanganese homeostasis by Kufor-Rakeb syndrome-associatedATP13A2 proteinrdquo Journal of Biological Chemistry vol 286 no34 pp 29654ndash29662 2011
[60] D Berg andHHochstrasser ldquoIronmetabolism in parkinsoniansyndromesrdquo Movement Disorders vol 21 no 9 pp 1299ndash13102006
[61] A E Oakley J F Collingwood J Dobson et al ldquoIndividualdopaminergic neurons show raised iron levels in Parkinsondiseaserdquo Neurology vol 68 no 21 pp 1820ndash1825 2007
[62] D Devos C Moreau and J C Devedjian ldquoTargeting chelatableiron as a therapeutic modality in Parkinsonrsquos diseaserdquo Antioxi-dants and Redox Signaling vol 21 no 2 pp 195ndash210 2014
[63] M Poli M Derosas S Luscieti et al ldquoPantothenate kinase-2 (Pank2) silencing causes cell growth reduction cell-specificferroportin upregulation and iron deregulationrdquo Neurobiologyof Disease vol 39 no 2 pp 204ndash210 2010
[64] T Tsunemi and D Krainc ldquoZn2+ dyshomeostasis caused by lossof ATP13A2PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulationrdquo Human Molecular Genetics vol 23no 11 pp 2791ndash2801 2014
[65] J Xu E Marzetti A Y Seo J Kim T A Prolla and CLeeuwenburgh ldquoThe emerging role of iron dyshomeostasis inthe mitochondrial decay of agingrdquo Mechanisms of Ageing andDevelopment vol 131 no 7-8 pp 487ndash493 2010
[66] M B H Youdim and P Riederer ldquoThe role of iron in senescenceof dopaminergic neurons in Parkinsonrsquos diseaserdquo Journal ofNeural Transmission Supplement no 40 pp 57ndash67 1993
[67] P Karki E Lee and M Aschner ldquoManganese neurotoxicity afocus on glutamate transportersrdquo Annals of Occupational andEnvironmental Medicine vol 25 no 1 article 4 2013
[68] H H Goebel L Gerhard E Kominami and M Hal-tia ldquoNeuronal ceroid-lipofuscinosismdashlate-infantile or Jansky-Bielschowsky typemdashrevisitedrdquo Brain Pathology vol 6 no 3 pp225ndash228 1996
[69] A Wohlke U Philipp P Bock et al ldquoA one base pair deletionin the canine ATP13A2 gene causes exon skipping and late-onset neuronal ceroid lipofuscinosis in the Tibetan terrierrdquoPLoS Genetics vol 7 no 10 Article ID e1002304 2011
[70] F H G Farias R Zeng G S Johnson et al ldquoA truncatingmuta-tion in ATP13A2 is responsible for adult-onset neuronal ceroidlipofuscinosis in Tibetan terriersrdquo Neurobiology of Disease vol42 no 3 pp 468ndash474 2011
[71] P J Schultheis S M Fleming A K Clippinger et al ldquoAtp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis limited120572-synuclein accumulation and age-dependent sensorimotordeficitsrdquo Human Molecular Genetics vol 22 no 10 pp 2067ndash2082 2013
[72] J G Burneo T Arnold C A Palmer R I Kuzniecky SJ Oh and E Faught ldquoAdult-onset neuronal ceroid lipofusci-nosis (Kufs disease) with autosomal dominant inheritance inAlabamardquo Epilepsia vol 44 no 6 pp 841ndash846 2003
[73] S F Berkovic S Carpenter F Andermann E Andermann andL S Wolfe ldquoKufsrsquo disease a critical reappraisalrdquo Brain vol 111no 1 part 1 pp 27ndash62 1988
[74] P C G Nijssen E Brusse A C M Leyten J J Martin JL J M Teepen and R A C Roos ldquoAutosomal dominantadult neuronal ceroid lipofuscinosis parkinsonism due to bothstriatal and nigral dysfunctionrdquoMovement Disorders vol 17 no3 pp 482ndash487 2002
[75] P E M Taschner N de Vos A D Thompson et al ldquoChro-mosome 16 microdeletion in a patient with juvenile neuronalceroid lipofuscinosis (Batten disease)rdquoThe American Journal ofHuman Genetics vol 56 no 3 pp 663ndash668 1995
[76] A Y Lavrov E S Ilyna E Y Zakharova A M Boukina andS V Tishkanina ldquoThe first three Russian cases of classical late-infantile neuronal ceroid lipofuscinosisrdquo European Journal ofPaediatric Neurology vol 6 no 3 pp 161ndash164 2002
[77] J Bras A Singleton M R Cookson and J Hardy ldquoEmerg-ing pathways in genetic Parkinsonrsquos disease potential role ofceramide metabolism in Lewy body diseaserdquo FEBS Journal vol275 no 23 pp 5767ndash5773 2008
[78] S El Haddad M Khoury M Daoud et al ldquoCLN5 and CLN8protein association with ceramide synthase biochemical andproteomic approachesrdquoElectrophoresis vol 33 no 24 pp 3798ndash3809 2012
[79] D Persaud-Sawin T Mousallem C Wang A Zucker E Kom-inami and R N Boustany ldquoNeuronal ceroid lipofuscinosis acommon pathwayrdquo Pediatric Research vol 61 no 2 pp 146ndash152 2007
[80] T J van Ham K L Thijssen R Breitling R M W Hofstra RH A Plasterk and E A A Nollen ldquoC elegansmodel identifiesgenetic modifiers of 120572-synuclein inclusion formation duringagingrdquo PLoS Genetics vol 4 no 3 Article ID e1000027 2008
[81] A Halperin D Elstein and A Zimran ldquoIncreased incidenceof Parkinson disease among relatives of patients with Gaucherdiseaserdquo Blood Cells Molecules and Diseases vol 36 no 3 pp426ndash428 2006
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
International Journal of
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neuroscience Journal
Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Psychiatry Journal
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Brain ScienceInternational Journal of
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neurodegenerative Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International 7
for proper functioning of lysosomes and mitochondria andperhaps for clearance of divalent metals defects in any ofthese three processes are tightly associated with neurodegen-eration Nevertheless more studies are needed that directlyexamine how PD-associated mutations in ATP13A2 affectthe activity and localization of the protein and ultimatelythe integrity of these three processes ATP13A2 mutationsthat affect one of these processes lysosomal functioningmay simultaneously increase the risk of PD and NCLs Inotherwords these quite clinically different diseasesmay sharea mechanism of lysosomal dysfunction If further studiesvalidate the literature the ATP13A2 gene andor protein maybecome a suitable therapeutic target for treating both PD andNCLs
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Work by the authors related to this review was supportedby the Sichuan Key Project of Science and Technology (no2010SZ0086) and the National Natural Science Foundationof China (no 30700243)
References
[1] S Lesage and A Brice ldquoParkinsonrsquos disease from monogenicforms to genetic susceptibility factorsrdquo Human MolecularGenetics vol 18 no R1 pp R48ndashR59 2009
[2] V Bonifati ldquoGenetics of Parkinsonrsquos diseasemdashstate of the artrdquoParkinsonism amp Related Disorders vol 20 supplement 1 ppS23ndashS28 2014
[3] F Coppede ldquoGenetics and epigenetics of Parkinsonrsquos diseaserdquoScientific World Journal vol 2012 Article ID 489830 12 pages2012
[4] S Lesage E Lohmann F Tison F Durif A Durr and ABrice ldquoGene symbol PARK2 Disease parkinsonism juvenileautosomal recessiverdquoHuman genetics vol 123 no 1 article 1142008
[5] V Bonifati P Rizzu M J Van Baren et al ldquoMutations inthe DJ-1 gene associated with autosomal recessive early-onsetparkinsonismrdquo Science vol 299 no 5604 pp 256ndash259 2003
[6] Y Li H Tomiyama K Sato et al ldquoClinicogenetic study ofPINK1mutations in autosomal recessive early-onset parkinson-ismrdquo Neurology vol 64 no 11 pp 1955ndash1957 2005
[7] A Ramirez A Heimbach J Grundemann et al ldquoHeredi-tary parkinsonism with dementia is caused by mutations inATP13A2 encoding a lysosomal type 5 P-type ATPaserdquo NatureGenetics vol 38 no 10 pp 1184ndash1191 2006
[8] H Tomiyama H Yoshino K Ogaki et al ldquoPLA2G6 variant inParkinsons diseaserdquo Journal of Human Genetics vol 56 no 5pp 401ndash403 2011
[9] A Di Fonzo M C J Dekker P Montagna et al ldquoFBXO7mutations cause autosomal recessive early-onset parkinsonian-pyramidal syndromerdquo Neurology vol 72 no 3 pp 240ndash2452009
[10] J Bras A Verloes S A Schneider S E Mole and R J Guer-reiro ldquoMutation of the parkinsonism gene ATP13A2 causesneuronal ceroid-lipofuscinosisrdquo Human Molecular Geneticsvol 21 no 12 pp 2646ndash2650 2012
[11] A Di Fonzo H F Chien M Socal et al ldquoATP13A2 missensemutations in juvenile Parkinsonism and young onset Parkinsondiseaserdquo Neurology vol 68 no 19 pp 1557ndash1562 2007
[12] Y P Ning K Kanai H Tomiyama et al ldquoPARK9-linkedparkinsonism in eastern Asia mutation detection in ATP13A2and clinical phenotyperdquo Neurology vol 70 no 16 part 2 pp1491ndash1493 2008
[13] M Funayama H Tomiyama R M Wu et al ldquoRapid screeningof ATP13A2 variant with highresolution melting analysisrdquoMovement Disorders vol 25 no 14 pp 2434ndash2437 2010
[14] C H Lin E K Tan M L Chen et al ldquoNovel ATP13A2 variantassociated with Parkinson disease in Taiwan and SingaporerdquoNeurology vol 71 no 21 pp 1727ndash1732 2008
[15] C-M Chen C-H Lin H-F Juan et al ldquoATP13A2 variabilityin Taiwanese Parkinsonrsquos diseaserdquo American Journal of MedicalGenetics B Neuropsychiatric Genetics vol 156 no 6 pp 720ndash729 2011
[16] J Park PMehta A A Cooper et al ldquoPathogenic effects of novelmutations in the P-type ATPase ATP13A2 (PARK9) causingKufor-Rakeb syndrome a form of early-onset parkinsonismrdquoHuman Mutation vol 32 no 8 pp 956ndash964 2011
[17] L H Zhu X G Luo Y S Zhou et al ldquoLack of associationbetween three single nucleotide polymorphisms in the PARK9PARK15 and BST1 genes and Parkinsonrsquos disease in the north-ern Han Chinese populationrdquo Chinese Medical Journal vol 125no 4 pp 588ndash592 2012
[18] A Djarmati J Hagenah K Reetz et al ldquoATP13A2 variants inearly-onset Parkinsonrsquos disease patients and controlsrdquo Move-ment Disorders vol 24 no 14 pp 2104ndash2111 2009
[19] M Malakouti-Nejad G A Shahidi M Rohani et al ldquoIdenti-fication of pGln858lowast in ATP13A2 in two EOPD patients andpresentation of their clinical featuresrdquoNeuroscience Letters vol577 pp 106ndash111 2014
[20] S A Schneider C Paisan-Ruiz N P Quinn et al ldquoATP13A2mutations (PARK9) cause neurodegeneration with brain ironaccumulationrdquoMovement Disorders vol 25 no 8 pp 979ndash9842010
[21] C Y Fong A Rolfs T Schwarzbraun C Klein and F J KOrsquoCallaghan ldquoJuvenile parkinsonism associated with heterozy-gous frameshift ATP13A2 gene mutationrdquo European Journal ofPaediatric Neurology vol 15 no 3 pp 271ndash275 2011
[22] D Crosiers B Ceulemans B Meeus et al ldquoJuvenile dystonia-parkinsonism and dementia caused by a novel ATP13A2frameshift mutationrdquo Parkinsonism and Related Disorders vol17 no 2 pp 135ndash138 2011
[23] H Eiberg L Hansen L Korbo et al ldquoNovel mutation inATP13A2 widens the spectrum of Kufor-Rakeb syndrome(PARK9)rdquo Clinical Genetics vol 82 no 3 pp 256ndash263 2012
[24] L Santoro G J Breedveld F Manganelli et al ldquoNovelATP13A2(PARK9) homozygous mutation in a family with markedphenotype variabilityrdquo Neurogenetics vol 12 no 1 pp 33ndash392011
[25] Q Z Fei L Cao Q Xiao et al ldquoLack of association betweenATP13A2 Ala746Thr variant and Parkinsons disease in Hanpopulation of mainland Chinardquo Neuroscience Letters vol 475no 2 pp 61ndash63 2010
8 BioMed Research International
[26] X Y Mao J M Burgunder Z J Zhang et al ldquoATP13A2G2236A variant is rare in patients with early-onset Parkinsonrsquosdisease and familial Parkinsonrsquos disease from mainland ChinardquoParkinsonism and Related Disorders vol 16 no 3 pp 235ndash2362010
[27] A Y Y Chan L Baum N L S Tang et al ldquoThe role ofthe Ala746Thr variant in the ATP13A2 gene among Chinesepatients with Parkinsonrsquos diseaserdquo Journal of Clinical Neuro-science vol 20 no 5 pp 761ndash762 2013
[28] H Darvish A Movafagh M D Omrani et al ldquoDetectionof copy number changes in genes associated with Parkinsonrsquosdisease in Iranian patientsrdquo Neuroscience Letters vol 551 pp75ndash78 2013
[29] C Vilarino-Guell A I Soto S J Lincoln et al ldquoATP13A2variability in Parkinson diseaserdquo Human Mutation vol 30 no3 pp 406ndash410 2009
[30] A Rakovic B Stiller A Djarmati et al ldquoGenetic associationstudy of the P-type ATPase ATP13A2 in late-onset ParkinsonrsquosdiseaserdquoMovement Disorders vol 24 no 3 pp 429ndash433 2009
[31] A S Najim Al-Din A Wriekat A Mubaidin M Dasoukiand M Hiari ldquoPallido-pyramidal degeneration supranuclearupgaze paresis and dementia Kufor-Rakeb syndromerdquo ActaNeurologica Scandinavica vol 89 no 5 pp 347ndash352 1994
[32] D R Williams A Hadeed A S Najim al-Din A Wreikatand A J Lees ldquoKufor Rakeb disease autosomal recessivelevodopa-responsive Parkinsonism with pyramidal degenera-tion supranuclear gaze palsy and dementiardquoMovement Disor-ders vol 20 no 10 pp 1264ndash1271 2005
[33] M I Behrens N Bruggemann P Chana et al ldquoClinicalspectrum of Kufor-Rakeb syndrome in the Chilean kindredwith ATP13A2 mutationsrdquoMovement Disorders vol 25 no 12pp 1929ndash1937 2010
[34] P J Schultheis T T Hagen K K OrsquoToole et al ldquoCharacteriza-tion of the P5 subfamily of P-type transport ATPases in micerdquoBiochemical and Biophysical Research Communications vol 323no 3 pp 731ndash738 2004
[35] B Schroder CWrocklage C Pan et al ldquoIntegral and associatedlysosomal membrane proteinsrdquo Traffic vol 8 no 12 pp 1676ndash1686 2007
[36] H Matsui F Sato S Sato et al ldquoATP13A2 deficiency inducesa decrease in cathepsin D activity fingerprint-like inclusionbody formation and selective degeneration of dopaminergicneuronsrdquo FEBS Letters vol 587 no 9 pp 1316ndash1325 2013
[37] B Dehay A Ramirez M Martinez-Vicente et al ldquoLoss of P-type ATPase ATP13A2PARK9 function induces general lyso-somal deficiency and leads to Parkinson disease neurodegen-erationrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 109 no 24 pp 9611ndash9616 2012
[38] K E Murphy L Cottle A M Gysbers A A Cooper and GM Halliday ldquoATP13A2 (PARK9) protein levels are reduced inbrain tissue of cases with Lewy bodiesrdquo Acta NeuropathologicaCommunications vol 1 article 11 2013
[39] G K Tofaris ldquoLysosome-dependent pathways as a unifyingtheme in Parkinsonrsquos diseaserdquo Movement Disorders vol 27 no11 pp 1364ndash1369 2012
[40] S M Kong B K Chan J S Park et al ldquoParkinsonrsquos disease-linked human PARK9 ATP13A2 maintains zinc homeosta-sis and promotes 120572-Synuclein externalization via exosomesrdquoHuman Molecular Genetics vol 23 no 11 pp 2816ndash2833 2014
[41] A D Gitler A Chesi M L Geddie et al ldquo120572-Synuclein ispart of a diverse and highly conserved interaction network that
includes PARK9 and manganese toxicityrdquo Nature Genetics vol41 no 3 pp 308ndash315 2009
[42] M Usenovic E Tresse J R Mazzulli J P Taylor and DKrainc ldquoDeficiency ofATP13A2 leads to lysosomal dysfunction120572-synuclein accumulation and neurotoxicityrdquo The Journal ofNeuroscience vol 32 no 12 pp 4240ndash4246 2012
[43] J S Park B Koentjoro D Veivers A Mackay-Sim and C MSue ldquoParkinsonrsquos disease-associated human ATP13A2 (PARK9)deficiency causes zinc dyshomeostasis andmitochondrial dys-functionrdquo Human Molecular Genetics vol 23 no 11 pp 2802ndash2815 2014
[44] A M Gusdon J Zhu B van Houten and C T ChuldquoATP13A2 regulates mitochondrial bioenergetics throughmacroautophagyrdquo Neurobiology of Disease vol 45 no 3 pp962ndash972 2012
[45] D Ramonet A Podhajska K Stafa et al ldquoPARK9-associatedATP13A2 localizes to intracellular acidic vesicles and regulatescation homeostasis and neuronal integrityrdquo Human MolecularGenetics vol 21 no 8 pp 1725ndash1743 2012
[46] R A Nixon D S Yang and J H Lee ldquoNeurodegenerativelysosomal disorders a continuum from development to lateagerdquo Autophagy vol 4 no 5 pp 590ndash599 2008
[47] B Dehay M Martinez-Vicente G A Caldwell et al ldquoLysoso-mal impairment in Parkinsonrsquos diseaserdquo Movement Disordersvol 28 no 6 pp 725ndash732 2013
[48] C W Olanow and P Brundin ldquoParkinsonrsquos disease and alphasynuclein is Parkinsonrsquos disease a prion-like disorderrdquo Move-ment Disorders vol 28 no 1 pp 31ndash40 2013
[49] J Bove M Martınez-Vicente and M Vila ldquoFighting neu-rodegeneration with rapamycin mechanistic insightsrdquo NatureReviews Neuroscience vol 12 no 8 pp 437ndash452 2011
[50] K Schmidt D M Wolfe B Stiller and D A Pearce ldquoCd2+Mn2+ Ni2+ and Se2+ toxicity to Saccharomyces cerevisiaelacking YPK9p the orthologue of human ATP13A2rdquo Biochem-ical and Biophysical Research Communications vol 383 no 2pp 198ndash202 2009
[51] P G Mastroberardino E K Hoffman M P Horowitz et al ldquoAnovel transferrinTfR2-mediated mitochondrial iron transportsystem is disrupted in Parkinsonrsquos diseaserdquo Neurobiology ofDisease vol 34 no 3 pp 417ndash431 2009
[52] C T Sheline J Zhu W Zhang C Shi and A Cai ldquoMitochon-drial inhibitor models of Huntingtonrsquos disease and Parkinsonrsquosdisease induce zinc accumulation and are attenuated by inhibi-tion of zinc neurotoxicity in vitro or in vivordquoNeurodegenerativeDiseases vol 11 no 1 pp 49ndash58 2013
[53] T Fukushima X Tan Y Luo and H Kanda ldquoSerum vitaminsand heavy metals in blood and urine and the correlationsamong them in parkinsonrsquos disease patients inChinardquoNeuroepi-demiology vol 36 no 4 pp 240ndash244 2011
[54] I Hozumi T Hasegawa A Honda et al ldquoPatterns of levelsof biological metals in CSF differ among neurodegenerativediseasesrdquo Journal of the Neurological Sciences vol 303 no 1-2pp 95ndash99 2011
[55] F J Jimenez-Jimenez P Fernandez-Calle M Martınez-Vanaclocha et al ldquoSerum levels of zinc and copper in patientswith Parkinsonrsquos diseaserdquo Journal of the Neurological Sciencesvol 112 no 1-2 pp 30ndash33 1992
[56] T R Guilarte ldquoManganese and Parkinsonrsquos disease a criticalreview and new findingsrdquo Environmental Health Perspectivesvol 118 no 8 pp 1071ndash1080 2010
BioMed Research International 9
[57] P Pals B van Everbroeck B Grubben et al ldquoCase-controlstudy of environmental risk factors for Parkinsonrsquos disease inBelgiumrdquo European Journal of Epidemiology vol 18 no 12 pp1133ndash1142 2003
[58] G Rentschler L Covolo A Ahmadi Haddad R G LucchiniS Zoni and K Broberg ldquoATP13A2 (PARK9) polymorphismsinfluence the neurotoxic effects of manganeserdquo NeuroToxicol-ogy vol 33 no 4 pp 697ndash702 2012
[59] J Tan T Zhang L Jiang et al ldquoRegulation of intracellularmanganese homeostasis by Kufor-Rakeb syndrome-associatedATP13A2 proteinrdquo Journal of Biological Chemistry vol 286 no34 pp 29654ndash29662 2011
[60] D Berg andHHochstrasser ldquoIronmetabolism in parkinsoniansyndromesrdquo Movement Disorders vol 21 no 9 pp 1299ndash13102006
[61] A E Oakley J F Collingwood J Dobson et al ldquoIndividualdopaminergic neurons show raised iron levels in Parkinsondiseaserdquo Neurology vol 68 no 21 pp 1820ndash1825 2007
[62] D Devos C Moreau and J C Devedjian ldquoTargeting chelatableiron as a therapeutic modality in Parkinsonrsquos diseaserdquo Antioxi-dants and Redox Signaling vol 21 no 2 pp 195ndash210 2014
[63] M Poli M Derosas S Luscieti et al ldquoPantothenate kinase-2 (Pank2) silencing causes cell growth reduction cell-specificferroportin upregulation and iron deregulationrdquo Neurobiologyof Disease vol 39 no 2 pp 204ndash210 2010
[64] T Tsunemi and D Krainc ldquoZn2+ dyshomeostasis caused by lossof ATP13A2PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulationrdquo Human Molecular Genetics vol 23no 11 pp 2791ndash2801 2014
[65] J Xu E Marzetti A Y Seo J Kim T A Prolla and CLeeuwenburgh ldquoThe emerging role of iron dyshomeostasis inthe mitochondrial decay of agingrdquo Mechanisms of Ageing andDevelopment vol 131 no 7-8 pp 487ndash493 2010
[66] M B H Youdim and P Riederer ldquoThe role of iron in senescenceof dopaminergic neurons in Parkinsonrsquos diseaserdquo Journal ofNeural Transmission Supplement no 40 pp 57ndash67 1993
[67] P Karki E Lee and M Aschner ldquoManganese neurotoxicity afocus on glutamate transportersrdquo Annals of Occupational andEnvironmental Medicine vol 25 no 1 article 4 2013
[68] H H Goebel L Gerhard E Kominami and M Hal-tia ldquoNeuronal ceroid-lipofuscinosismdashlate-infantile or Jansky-Bielschowsky typemdashrevisitedrdquo Brain Pathology vol 6 no 3 pp225ndash228 1996
[69] A Wohlke U Philipp P Bock et al ldquoA one base pair deletionin the canine ATP13A2 gene causes exon skipping and late-onset neuronal ceroid lipofuscinosis in the Tibetan terrierrdquoPLoS Genetics vol 7 no 10 Article ID e1002304 2011
[70] F H G Farias R Zeng G S Johnson et al ldquoA truncatingmuta-tion in ATP13A2 is responsible for adult-onset neuronal ceroidlipofuscinosis in Tibetan terriersrdquo Neurobiology of Disease vol42 no 3 pp 468ndash474 2011
[71] P J Schultheis S M Fleming A K Clippinger et al ldquoAtp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis limited120572-synuclein accumulation and age-dependent sensorimotordeficitsrdquo Human Molecular Genetics vol 22 no 10 pp 2067ndash2082 2013
[72] J G Burneo T Arnold C A Palmer R I Kuzniecky SJ Oh and E Faught ldquoAdult-onset neuronal ceroid lipofusci-nosis (Kufs disease) with autosomal dominant inheritance inAlabamardquo Epilepsia vol 44 no 6 pp 841ndash846 2003
[73] S F Berkovic S Carpenter F Andermann E Andermann andL S Wolfe ldquoKufsrsquo disease a critical reappraisalrdquo Brain vol 111no 1 part 1 pp 27ndash62 1988
[74] P C G Nijssen E Brusse A C M Leyten J J Martin JL J M Teepen and R A C Roos ldquoAutosomal dominantadult neuronal ceroid lipofuscinosis parkinsonism due to bothstriatal and nigral dysfunctionrdquoMovement Disorders vol 17 no3 pp 482ndash487 2002
[75] P E M Taschner N de Vos A D Thompson et al ldquoChro-mosome 16 microdeletion in a patient with juvenile neuronalceroid lipofuscinosis (Batten disease)rdquoThe American Journal ofHuman Genetics vol 56 no 3 pp 663ndash668 1995
[76] A Y Lavrov E S Ilyna E Y Zakharova A M Boukina andS V Tishkanina ldquoThe first three Russian cases of classical late-infantile neuronal ceroid lipofuscinosisrdquo European Journal ofPaediatric Neurology vol 6 no 3 pp 161ndash164 2002
[77] J Bras A Singleton M R Cookson and J Hardy ldquoEmerg-ing pathways in genetic Parkinsonrsquos disease potential role ofceramide metabolism in Lewy body diseaserdquo FEBS Journal vol275 no 23 pp 5767ndash5773 2008
[78] S El Haddad M Khoury M Daoud et al ldquoCLN5 and CLN8protein association with ceramide synthase biochemical andproteomic approachesrdquoElectrophoresis vol 33 no 24 pp 3798ndash3809 2012
[79] D Persaud-Sawin T Mousallem C Wang A Zucker E Kom-inami and R N Boustany ldquoNeuronal ceroid lipofuscinosis acommon pathwayrdquo Pediatric Research vol 61 no 2 pp 146ndash152 2007
[80] T J van Ham K L Thijssen R Breitling R M W Hofstra RH A Plasterk and E A A Nollen ldquoC elegansmodel identifiesgenetic modifiers of 120572-synuclein inclusion formation duringagingrdquo PLoS Genetics vol 4 no 3 Article ID e1000027 2008
[81] A Halperin D Elstein and A Zimran ldquoIncreased incidenceof Parkinson disease among relatives of patients with Gaucherdiseaserdquo Blood Cells Molecules and Diseases vol 36 no 3 pp426ndash428 2006
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
International Journal of
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neuroscience Journal
Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Psychiatry Journal
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Brain ScienceInternational Journal of
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neurodegenerative Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
8 BioMed Research International
[26] X Y Mao J M Burgunder Z J Zhang et al ldquoATP13A2G2236A variant is rare in patients with early-onset Parkinsonrsquosdisease and familial Parkinsonrsquos disease from mainland ChinardquoParkinsonism and Related Disorders vol 16 no 3 pp 235ndash2362010
[27] A Y Y Chan L Baum N L S Tang et al ldquoThe role ofthe Ala746Thr variant in the ATP13A2 gene among Chinesepatients with Parkinsonrsquos diseaserdquo Journal of Clinical Neuro-science vol 20 no 5 pp 761ndash762 2013
[28] H Darvish A Movafagh M D Omrani et al ldquoDetectionof copy number changes in genes associated with Parkinsonrsquosdisease in Iranian patientsrdquo Neuroscience Letters vol 551 pp75ndash78 2013
[29] C Vilarino-Guell A I Soto S J Lincoln et al ldquoATP13A2variability in Parkinson diseaserdquo Human Mutation vol 30 no3 pp 406ndash410 2009
[30] A Rakovic B Stiller A Djarmati et al ldquoGenetic associationstudy of the P-type ATPase ATP13A2 in late-onset ParkinsonrsquosdiseaserdquoMovement Disorders vol 24 no 3 pp 429ndash433 2009
[31] A S Najim Al-Din A Wriekat A Mubaidin M Dasoukiand M Hiari ldquoPallido-pyramidal degeneration supranuclearupgaze paresis and dementia Kufor-Rakeb syndromerdquo ActaNeurologica Scandinavica vol 89 no 5 pp 347ndash352 1994
[32] D R Williams A Hadeed A S Najim al-Din A Wreikatand A J Lees ldquoKufor Rakeb disease autosomal recessivelevodopa-responsive Parkinsonism with pyramidal degenera-tion supranuclear gaze palsy and dementiardquoMovement Disor-ders vol 20 no 10 pp 1264ndash1271 2005
[33] M I Behrens N Bruggemann P Chana et al ldquoClinicalspectrum of Kufor-Rakeb syndrome in the Chilean kindredwith ATP13A2 mutationsrdquoMovement Disorders vol 25 no 12pp 1929ndash1937 2010
[34] P J Schultheis T T Hagen K K OrsquoToole et al ldquoCharacteriza-tion of the P5 subfamily of P-type transport ATPases in micerdquoBiochemical and Biophysical Research Communications vol 323no 3 pp 731ndash738 2004
[35] B Schroder CWrocklage C Pan et al ldquoIntegral and associatedlysosomal membrane proteinsrdquo Traffic vol 8 no 12 pp 1676ndash1686 2007
[36] H Matsui F Sato S Sato et al ldquoATP13A2 deficiency inducesa decrease in cathepsin D activity fingerprint-like inclusionbody formation and selective degeneration of dopaminergicneuronsrdquo FEBS Letters vol 587 no 9 pp 1316ndash1325 2013
[37] B Dehay A Ramirez M Martinez-Vicente et al ldquoLoss of P-type ATPase ATP13A2PARK9 function induces general lyso-somal deficiency and leads to Parkinson disease neurodegen-erationrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 109 no 24 pp 9611ndash9616 2012
[38] K E Murphy L Cottle A M Gysbers A A Cooper and GM Halliday ldquoATP13A2 (PARK9) protein levels are reduced inbrain tissue of cases with Lewy bodiesrdquo Acta NeuropathologicaCommunications vol 1 article 11 2013
[39] G K Tofaris ldquoLysosome-dependent pathways as a unifyingtheme in Parkinsonrsquos diseaserdquo Movement Disorders vol 27 no11 pp 1364ndash1369 2012
[40] S M Kong B K Chan J S Park et al ldquoParkinsonrsquos disease-linked human PARK9 ATP13A2 maintains zinc homeosta-sis and promotes 120572-Synuclein externalization via exosomesrdquoHuman Molecular Genetics vol 23 no 11 pp 2816ndash2833 2014
[41] A D Gitler A Chesi M L Geddie et al ldquo120572-Synuclein ispart of a diverse and highly conserved interaction network that
includes PARK9 and manganese toxicityrdquo Nature Genetics vol41 no 3 pp 308ndash315 2009
[42] M Usenovic E Tresse J R Mazzulli J P Taylor and DKrainc ldquoDeficiency ofATP13A2 leads to lysosomal dysfunction120572-synuclein accumulation and neurotoxicityrdquo The Journal ofNeuroscience vol 32 no 12 pp 4240ndash4246 2012
[43] J S Park B Koentjoro D Veivers A Mackay-Sim and C MSue ldquoParkinsonrsquos disease-associated human ATP13A2 (PARK9)deficiency causes zinc dyshomeostasis andmitochondrial dys-functionrdquo Human Molecular Genetics vol 23 no 11 pp 2802ndash2815 2014
[44] A M Gusdon J Zhu B van Houten and C T ChuldquoATP13A2 regulates mitochondrial bioenergetics throughmacroautophagyrdquo Neurobiology of Disease vol 45 no 3 pp962ndash972 2012
[45] D Ramonet A Podhajska K Stafa et al ldquoPARK9-associatedATP13A2 localizes to intracellular acidic vesicles and regulatescation homeostasis and neuronal integrityrdquo Human MolecularGenetics vol 21 no 8 pp 1725ndash1743 2012
[46] R A Nixon D S Yang and J H Lee ldquoNeurodegenerativelysosomal disorders a continuum from development to lateagerdquo Autophagy vol 4 no 5 pp 590ndash599 2008
[47] B Dehay M Martinez-Vicente G A Caldwell et al ldquoLysoso-mal impairment in Parkinsonrsquos diseaserdquo Movement Disordersvol 28 no 6 pp 725ndash732 2013
[48] C W Olanow and P Brundin ldquoParkinsonrsquos disease and alphasynuclein is Parkinsonrsquos disease a prion-like disorderrdquo Move-ment Disorders vol 28 no 1 pp 31ndash40 2013
[49] J Bove M Martınez-Vicente and M Vila ldquoFighting neu-rodegeneration with rapamycin mechanistic insightsrdquo NatureReviews Neuroscience vol 12 no 8 pp 437ndash452 2011
[50] K Schmidt D M Wolfe B Stiller and D A Pearce ldquoCd2+Mn2+ Ni2+ and Se2+ toxicity to Saccharomyces cerevisiaelacking YPK9p the orthologue of human ATP13A2rdquo Biochem-ical and Biophysical Research Communications vol 383 no 2pp 198ndash202 2009
[51] P G Mastroberardino E K Hoffman M P Horowitz et al ldquoAnovel transferrinTfR2-mediated mitochondrial iron transportsystem is disrupted in Parkinsonrsquos diseaserdquo Neurobiology ofDisease vol 34 no 3 pp 417ndash431 2009
[52] C T Sheline J Zhu W Zhang C Shi and A Cai ldquoMitochon-drial inhibitor models of Huntingtonrsquos disease and Parkinsonrsquosdisease induce zinc accumulation and are attenuated by inhibi-tion of zinc neurotoxicity in vitro or in vivordquoNeurodegenerativeDiseases vol 11 no 1 pp 49ndash58 2013
[53] T Fukushima X Tan Y Luo and H Kanda ldquoSerum vitaminsand heavy metals in blood and urine and the correlationsamong them in parkinsonrsquos disease patients inChinardquoNeuroepi-demiology vol 36 no 4 pp 240ndash244 2011
[54] I Hozumi T Hasegawa A Honda et al ldquoPatterns of levelsof biological metals in CSF differ among neurodegenerativediseasesrdquo Journal of the Neurological Sciences vol 303 no 1-2pp 95ndash99 2011
[55] F J Jimenez-Jimenez P Fernandez-Calle M Martınez-Vanaclocha et al ldquoSerum levels of zinc and copper in patientswith Parkinsonrsquos diseaserdquo Journal of the Neurological Sciencesvol 112 no 1-2 pp 30ndash33 1992
[56] T R Guilarte ldquoManganese and Parkinsonrsquos disease a criticalreview and new findingsrdquo Environmental Health Perspectivesvol 118 no 8 pp 1071ndash1080 2010
BioMed Research International 9
[57] P Pals B van Everbroeck B Grubben et al ldquoCase-controlstudy of environmental risk factors for Parkinsonrsquos disease inBelgiumrdquo European Journal of Epidemiology vol 18 no 12 pp1133ndash1142 2003
[58] G Rentschler L Covolo A Ahmadi Haddad R G LucchiniS Zoni and K Broberg ldquoATP13A2 (PARK9) polymorphismsinfluence the neurotoxic effects of manganeserdquo NeuroToxicol-ogy vol 33 no 4 pp 697ndash702 2012
[59] J Tan T Zhang L Jiang et al ldquoRegulation of intracellularmanganese homeostasis by Kufor-Rakeb syndrome-associatedATP13A2 proteinrdquo Journal of Biological Chemistry vol 286 no34 pp 29654ndash29662 2011
[60] D Berg andHHochstrasser ldquoIronmetabolism in parkinsoniansyndromesrdquo Movement Disorders vol 21 no 9 pp 1299ndash13102006
[61] A E Oakley J F Collingwood J Dobson et al ldquoIndividualdopaminergic neurons show raised iron levels in Parkinsondiseaserdquo Neurology vol 68 no 21 pp 1820ndash1825 2007
[62] D Devos C Moreau and J C Devedjian ldquoTargeting chelatableiron as a therapeutic modality in Parkinsonrsquos diseaserdquo Antioxi-dants and Redox Signaling vol 21 no 2 pp 195ndash210 2014
[63] M Poli M Derosas S Luscieti et al ldquoPantothenate kinase-2 (Pank2) silencing causes cell growth reduction cell-specificferroportin upregulation and iron deregulationrdquo Neurobiologyof Disease vol 39 no 2 pp 204ndash210 2010
[64] T Tsunemi and D Krainc ldquoZn2+ dyshomeostasis caused by lossof ATP13A2PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulationrdquo Human Molecular Genetics vol 23no 11 pp 2791ndash2801 2014
[65] J Xu E Marzetti A Y Seo J Kim T A Prolla and CLeeuwenburgh ldquoThe emerging role of iron dyshomeostasis inthe mitochondrial decay of agingrdquo Mechanisms of Ageing andDevelopment vol 131 no 7-8 pp 487ndash493 2010
[66] M B H Youdim and P Riederer ldquoThe role of iron in senescenceof dopaminergic neurons in Parkinsonrsquos diseaserdquo Journal ofNeural Transmission Supplement no 40 pp 57ndash67 1993
[67] P Karki E Lee and M Aschner ldquoManganese neurotoxicity afocus on glutamate transportersrdquo Annals of Occupational andEnvironmental Medicine vol 25 no 1 article 4 2013
[68] H H Goebel L Gerhard E Kominami and M Hal-tia ldquoNeuronal ceroid-lipofuscinosismdashlate-infantile or Jansky-Bielschowsky typemdashrevisitedrdquo Brain Pathology vol 6 no 3 pp225ndash228 1996
[69] A Wohlke U Philipp P Bock et al ldquoA one base pair deletionin the canine ATP13A2 gene causes exon skipping and late-onset neuronal ceroid lipofuscinosis in the Tibetan terrierrdquoPLoS Genetics vol 7 no 10 Article ID e1002304 2011
[70] F H G Farias R Zeng G S Johnson et al ldquoA truncatingmuta-tion in ATP13A2 is responsible for adult-onset neuronal ceroidlipofuscinosis in Tibetan terriersrdquo Neurobiology of Disease vol42 no 3 pp 468ndash474 2011
[71] P J Schultheis S M Fleming A K Clippinger et al ldquoAtp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis limited120572-synuclein accumulation and age-dependent sensorimotordeficitsrdquo Human Molecular Genetics vol 22 no 10 pp 2067ndash2082 2013
[72] J G Burneo T Arnold C A Palmer R I Kuzniecky SJ Oh and E Faught ldquoAdult-onset neuronal ceroid lipofusci-nosis (Kufs disease) with autosomal dominant inheritance inAlabamardquo Epilepsia vol 44 no 6 pp 841ndash846 2003
[73] S F Berkovic S Carpenter F Andermann E Andermann andL S Wolfe ldquoKufsrsquo disease a critical reappraisalrdquo Brain vol 111no 1 part 1 pp 27ndash62 1988
[74] P C G Nijssen E Brusse A C M Leyten J J Martin JL J M Teepen and R A C Roos ldquoAutosomal dominantadult neuronal ceroid lipofuscinosis parkinsonism due to bothstriatal and nigral dysfunctionrdquoMovement Disorders vol 17 no3 pp 482ndash487 2002
[75] P E M Taschner N de Vos A D Thompson et al ldquoChro-mosome 16 microdeletion in a patient with juvenile neuronalceroid lipofuscinosis (Batten disease)rdquoThe American Journal ofHuman Genetics vol 56 no 3 pp 663ndash668 1995
[76] A Y Lavrov E S Ilyna E Y Zakharova A M Boukina andS V Tishkanina ldquoThe first three Russian cases of classical late-infantile neuronal ceroid lipofuscinosisrdquo European Journal ofPaediatric Neurology vol 6 no 3 pp 161ndash164 2002
[77] J Bras A Singleton M R Cookson and J Hardy ldquoEmerg-ing pathways in genetic Parkinsonrsquos disease potential role ofceramide metabolism in Lewy body diseaserdquo FEBS Journal vol275 no 23 pp 5767ndash5773 2008
[78] S El Haddad M Khoury M Daoud et al ldquoCLN5 and CLN8protein association with ceramide synthase biochemical andproteomic approachesrdquoElectrophoresis vol 33 no 24 pp 3798ndash3809 2012
[79] D Persaud-Sawin T Mousallem C Wang A Zucker E Kom-inami and R N Boustany ldquoNeuronal ceroid lipofuscinosis acommon pathwayrdquo Pediatric Research vol 61 no 2 pp 146ndash152 2007
[80] T J van Ham K L Thijssen R Breitling R M W Hofstra RH A Plasterk and E A A Nollen ldquoC elegansmodel identifiesgenetic modifiers of 120572-synuclein inclusion formation duringagingrdquo PLoS Genetics vol 4 no 3 Article ID e1000027 2008
[81] A Halperin D Elstein and A Zimran ldquoIncreased incidenceof Parkinson disease among relatives of patients with Gaucherdiseaserdquo Blood Cells Molecules and Diseases vol 36 no 3 pp426ndash428 2006
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
International Journal of
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neuroscience Journal
Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Psychiatry Journal
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Brain ScienceInternational Journal of
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neurodegenerative Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International 9
[57] P Pals B van Everbroeck B Grubben et al ldquoCase-controlstudy of environmental risk factors for Parkinsonrsquos disease inBelgiumrdquo European Journal of Epidemiology vol 18 no 12 pp1133ndash1142 2003
[58] G Rentschler L Covolo A Ahmadi Haddad R G LucchiniS Zoni and K Broberg ldquoATP13A2 (PARK9) polymorphismsinfluence the neurotoxic effects of manganeserdquo NeuroToxicol-ogy vol 33 no 4 pp 697ndash702 2012
[59] J Tan T Zhang L Jiang et al ldquoRegulation of intracellularmanganese homeostasis by Kufor-Rakeb syndrome-associatedATP13A2 proteinrdquo Journal of Biological Chemistry vol 286 no34 pp 29654ndash29662 2011
[60] D Berg andHHochstrasser ldquoIronmetabolism in parkinsoniansyndromesrdquo Movement Disorders vol 21 no 9 pp 1299ndash13102006
[61] A E Oakley J F Collingwood J Dobson et al ldquoIndividualdopaminergic neurons show raised iron levels in Parkinsondiseaserdquo Neurology vol 68 no 21 pp 1820ndash1825 2007
[62] D Devos C Moreau and J C Devedjian ldquoTargeting chelatableiron as a therapeutic modality in Parkinsonrsquos diseaserdquo Antioxi-dants and Redox Signaling vol 21 no 2 pp 195ndash210 2014
[63] M Poli M Derosas S Luscieti et al ldquoPantothenate kinase-2 (Pank2) silencing causes cell growth reduction cell-specificferroportin upregulation and iron deregulationrdquo Neurobiologyof Disease vol 39 no 2 pp 204ndash210 2010
[64] T Tsunemi and D Krainc ldquoZn2+ dyshomeostasis caused by lossof ATP13A2PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulationrdquo Human Molecular Genetics vol 23no 11 pp 2791ndash2801 2014
[65] J Xu E Marzetti A Y Seo J Kim T A Prolla and CLeeuwenburgh ldquoThe emerging role of iron dyshomeostasis inthe mitochondrial decay of agingrdquo Mechanisms of Ageing andDevelopment vol 131 no 7-8 pp 487ndash493 2010
[66] M B H Youdim and P Riederer ldquoThe role of iron in senescenceof dopaminergic neurons in Parkinsonrsquos diseaserdquo Journal ofNeural Transmission Supplement no 40 pp 57ndash67 1993
[67] P Karki E Lee and M Aschner ldquoManganese neurotoxicity afocus on glutamate transportersrdquo Annals of Occupational andEnvironmental Medicine vol 25 no 1 article 4 2013
[68] H H Goebel L Gerhard E Kominami and M Hal-tia ldquoNeuronal ceroid-lipofuscinosismdashlate-infantile or Jansky-Bielschowsky typemdashrevisitedrdquo Brain Pathology vol 6 no 3 pp225ndash228 1996
[69] A Wohlke U Philipp P Bock et al ldquoA one base pair deletionin the canine ATP13A2 gene causes exon skipping and late-onset neuronal ceroid lipofuscinosis in the Tibetan terrierrdquoPLoS Genetics vol 7 no 10 Article ID e1002304 2011
[70] F H G Farias R Zeng G S Johnson et al ldquoA truncatingmuta-tion in ATP13A2 is responsible for adult-onset neuronal ceroidlipofuscinosis in Tibetan terriersrdquo Neurobiology of Disease vol42 no 3 pp 468ndash474 2011
[71] P J Schultheis S M Fleming A K Clippinger et al ldquoAtp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis limited120572-synuclein accumulation and age-dependent sensorimotordeficitsrdquo Human Molecular Genetics vol 22 no 10 pp 2067ndash2082 2013
[72] J G Burneo T Arnold C A Palmer R I Kuzniecky SJ Oh and E Faught ldquoAdult-onset neuronal ceroid lipofusci-nosis (Kufs disease) with autosomal dominant inheritance inAlabamardquo Epilepsia vol 44 no 6 pp 841ndash846 2003
[73] S F Berkovic S Carpenter F Andermann E Andermann andL S Wolfe ldquoKufsrsquo disease a critical reappraisalrdquo Brain vol 111no 1 part 1 pp 27ndash62 1988
[74] P C G Nijssen E Brusse A C M Leyten J J Martin JL J M Teepen and R A C Roos ldquoAutosomal dominantadult neuronal ceroid lipofuscinosis parkinsonism due to bothstriatal and nigral dysfunctionrdquoMovement Disorders vol 17 no3 pp 482ndash487 2002
[75] P E M Taschner N de Vos A D Thompson et al ldquoChro-mosome 16 microdeletion in a patient with juvenile neuronalceroid lipofuscinosis (Batten disease)rdquoThe American Journal ofHuman Genetics vol 56 no 3 pp 663ndash668 1995
[76] A Y Lavrov E S Ilyna E Y Zakharova A M Boukina andS V Tishkanina ldquoThe first three Russian cases of classical late-infantile neuronal ceroid lipofuscinosisrdquo European Journal ofPaediatric Neurology vol 6 no 3 pp 161ndash164 2002
[77] J Bras A Singleton M R Cookson and J Hardy ldquoEmerg-ing pathways in genetic Parkinsonrsquos disease potential role ofceramide metabolism in Lewy body diseaserdquo FEBS Journal vol275 no 23 pp 5767ndash5773 2008
[78] S El Haddad M Khoury M Daoud et al ldquoCLN5 and CLN8protein association with ceramide synthase biochemical andproteomic approachesrdquoElectrophoresis vol 33 no 24 pp 3798ndash3809 2012
[79] D Persaud-Sawin T Mousallem C Wang A Zucker E Kom-inami and R N Boustany ldquoNeuronal ceroid lipofuscinosis acommon pathwayrdquo Pediatric Research vol 61 no 2 pp 146ndash152 2007
[80] T J van Ham K L Thijssen R Breitling R M W Hofstra RH A Plasterk and E A A Nollen ldquoC elegansmodel identifiesgenetic modifiers of 120572-synuclein inclusion formation duringagingrdquo PLoS Genetics vol 4 no 3 Article ID e1000027 2008
[81] A Halperin D Elstein and A Zimran ldquoIncreased incidenceof Parkinson disease among relatives of patients with Gaucherdiseaserdquo Blood Cells Molecules and Diseases vol 36 no 3 pp426ndash428 2006
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
International Journal of
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neuroscience Journal
Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Psychiatry Journal
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Brain ScienceInternational Journal of
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neurodegenerative Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Submit your manuscripts athttpwwwhindawicom
Neurology Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
International Journal of
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentSchizophrenia
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neural Plasticity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAutism
Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neuroscience Journal
Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Psychiatry Journal
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Brain ScienceInternational Journal of
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Neurodegenerative Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
