Etiopathogenesis of Parkinson’s Disease€¦ · • Alpha-synuclein gene (SNCA) ... (PMCA) and...
Transcript of Etiopathogenesis of Parkinson’s Disease€¦ · • Alpha-synuclein gene (SNCA) ... (PMCA) and...
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Joseph Jankovic, MDProfessor of Neurology, Distinguished Chair in Movement Disorders,
Director, Parkinson's Disease Center and Movement Disorders Clinic,
Department of Neurology, Baylor College of Medicine, Houston, Texas
Etiopathogenesis of Parkinson’s Disease
Jankovic J, Tan EK. JNNP 2020;91:795-808
GenesSNCA, PRKN, PINK1, DJ1,
LRRK2, etc;
susceptibility genes
(GBA, etc)
Environmentrural living, well water,
pesticides (rotenone, paraquat),
other toxins (MPTP)
Protective: smoking, coffee
PathogenesisSynuclein aggregation
and propagation
Excitotoxicity, inflammation,
mitochondrial dysfunction,
oxidative stress, axonopathy,
neurotrophic failure,
proteasomal and autophagy
dysfunction
Cell Death(SN and other nuclei)
PD
Etiology
Aging
Jankovic
Genetically-Determined Parkinsonism
Disease Inher.Gene Locus
(Gene)Protein
PARK-SNCA (PARK1) – typical PD AD4q21-23 (SNCA)A53T; A53E; A30P;
E46K; H50Q; G51D
α-synuclein
PARK-Parkin (PARK2) – early-onset, dystonia
AR6q25.2-27(PRKN, Parkin)
Ubiquitin ligase
PARK3 – typical PD AD 2p13 Unknown
PARK4 – parkinsonism, dementia, dysautonomia, postural tremor, LB, GCI
AD 4q21 α-synuclein triplication
PARK5 – PD AD4p14(UCH-L1)
Ubiquitin cyclohydrolase A
PARK-PINK1 (PARK6) – early-onset AR1p36(PINK1)
PTEN-induced kinase 1
PARK-DJ-1 (PARK7) – early-onset AR1p36(DJ-1)
DJ-1
PARK-LRRK2 (PARK8) – PD AD12p11.23-q13.11(LRRK2)
LARRK2 (Dardarin)
PARK-ATP13A2 (PARK9) (Kufor-Rakebsyndrome) – early-onset, levodopa-responsive, spasticity, dementia, ophthalmoparesis, pallidal atrophy, T2-striatal hypointensity
AR1p36
(ATP13A2)
Lysosomal type 5 P-type ATPase
Deng H, Wang P, Jankovic J. Ageing Res Rev 2018;42:72-85Marras et al. Mov Disord 2016;31:436-57
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Disease Inher.Gene Locus
(Gene)Protein
PARK10 – late-onset typical PD AD1p32 (4 genes in the locus) – Icelandic
?
PARK11 – middle-age AD2q36-37 (GIGYF2?) - North American
GRB10-interacting gyf protein 2
PARK12 – late onset PD X-linked Xq21-q25 ?
PARK13 – late onset typical PDAD
2p12
(HtrA2)Serine protease
NBIA/DYT/PARK-PLA2G6 (PARK14) –adult-onset dystonia-parkinsonism, subtype of NBIA
AR22q13.1
(PLA2G6)Phospholipase A2
PARK-FBXO7 (PARK15) – early-onset parkinsonian-pyramidal syndrome
AR22q12-q13
(FBXO7)
F-box
Protein7
PARK16 ? 1q32 – Japanese ?
PARK-VPS35 (PARK17) AD16q11.2
(VPS35)VPS35
PARK18 – typical PDAD
3q27
(EIF4G1)EIF4G1
PARK-DNAJC6 (PARK19) AR1p31.3
(DNAJC6) Auxilin
PARK-SYNJ1 (PARK20) AR21q22.11
(SYNJ1)Synaptojanin 1
Genetically-Determined Parkinsonism
Deng H, Wang P, Jankovic J. Ageing Res Rev 2018;42:72-85Marras et al. Mov Disord 2016;31:436-57
Disease Inher.Gene Locus
(Gene)Protein
PARK21 AD20p13
(TMEM230)
Transmembrane
protein TMEM230
PARK-CHCHD2 (PARK22) AD7p11.2
(CHCHD2)CHCHD2
PARK-VPS13C (PARK23) AR15q22.2
(VPS13C)
Vacuolar Protein
Sorting 13C
Other genetic parkinsonian disorders
Genetically-Determined Parkinsonism
Deng H, Wang P, Jankovic J. Ageing Res Rev 2018;42:72-85Marras et al. Mov Disord 2016;31:436-57
>100 GWAS signals explain 11-15% of the heritable risk of PD
Blauwendraat et al. Lancet Neurol 2020;19:170-8
Integrated exome sequencing and genome-wide array-based
comparative genomic hybridization yielded a genetic diagnosis in 19.3%
of Baylor’s familial PD cohort. Robak et al. Neurol Genet 2020;6:e498
Lancet Neurol 2019;18:1091-102
Manhattan Plot for Significant Variants
Genetically-Determined Parkinsonism
Disease Inher.Gene Locus
(Gene)Protein
PARK-SNCA (PARK1) – typical PD AD4q21-23 (SNCA)A53T; A53E; A30P;
E46K; H50Q; G51D
α-synuclein
PARK-Parkin (PARK2) – early-onset, dystonia
AR6q25.2-27(PRKN, Parkin)
Ubiquitin ligase
PARK3 – typical PD AD 2p13 Unknown
PARK4 – parkinsonism, dementia, dysautonomia, postural tremor, LB, GCI
AD 4q21 α-synuclein triplication
PARK5 – PD AD4p14(UCH-L1)
Ubiquitin cyclohydrolase A
PARK-PINK1 (PARK6) – early-onset AR1p36(PINK1)
PTEN-induced kinase 1
PARK-DJ-1 (PARK7) – early-onset AR1p36(DJ-1)
DJ-1
PARK-LRRK2 (PARK8) – PD AD12p11.23-q13.11(LRRK2)
LARRK2 (Dardarin)
PARK-ATP13A2 (PARK9) (Kufor-Rakebsyndrome) – early-onset, levodopa-responsive, spasticity, dementia, ophthalmoparesis, pallidal atrophy, T2-striatal hypointensity
AR1p36
(ATP13A2)
Lysosomal type 5 P-type ATPase
Deng H, Wang P, Jankovic J. Ageing Res Rev 2018;42:72-85Marras et al. Mov Disord 2016;31:436-57
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Alpha-Synuclein
Polymeropoulos MH, Higgins JJ, Golbe LI, Johnson WG, Ide SE, Di Iorio G, Sanges
G, Stenroos ES, Pho LT, Schaffer AA, Lazzarini AM, Nussbaum RL, Duvoisin RC. Mapping of a gene for Parkinson's disease to chromosome 4q21-q23.
Science 1996;274:1197-9
Genetic markers on chromosome 4q21-q23 were found to be linked to the PD phenotype in a large kindred with autosomal dominant PD. This finding will
facilitate identification of the gene and research on the pathogenesis of PD.
Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root
H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI,
Nussbaum RL. Mutation in the alpha-synuclein gene identified in families with
Parkinson's disease. Science 1997;276:2045-7
A mutation was identified in the alpha-synuclein gene, which codes for a
presynaptic protein thought to be involved in neuronal plasticity, in the Italian
kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype.
Alpha-Synuclein
• Alpha-synuclein gene (SNCA) – the 1st gene mutation identified to cause PD
phenotype (Italian-Greek families)
• Alpha-synuclein (140 AAs) is involved in 1. vesicle trafficking;
2. vesicle docking and priming; 3. vesicle fusion and neurotransmitter release
(involving SNARE protein complex); 4. axonal transport; etc
• Overexpression of alpha-synuclein in transgenic mice can cause levodopa-
responsive motor impairment and nigral degeneration
• Alpha-synuclein can cause toxicity by excessive amounts of wild-type
(multiplication), pathogenic mutations, and modification by dopamine (toxic
interactions between alpha-synuclein oligomers and lipids)
• Alpha-synuclein (non-soluble, aggregated, fibrillar form) is a major component
of Lewy bodies and Lewy neurites
• Phosphorylation of α-synuclein at Ser129 promotes insoluble fibril formation
and when cytosolic α-synuclein becomes phosphorylated, it eventually
becomes incorporated into Lewy neurites and Lewy bodies.
• Alpha-synuclein pathology spreads from PNS to CNS and from cell to cell
(Lewy pathology in transplanted fetal donor cells)
Clinical features associated with pathogenic SNCA mutations
Petrucci et al. Parkinsonism Relat Disord 2016;22 Suppl 1:S16-20
white → black ↑ severity
α-synuclein in Parkinson’s disease
Kalia. Parkinsonism Relat Disord 2019;59:21-5
Mor et al. Mov Disord 2019;34:167-79
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Discriminating α-synuclein strains in Parkinson's disease and multiple system atrophy
Gerez JA, Riek R. Nature 2020;578:223-4
Shahnawaz et al. Nature 2020;578:273-7
Walker. Nature 2018;557:499-500
α-synuclein aggregates that are associated with PD and MSA correspond to different conformational strains of α-synuclein Rietdijk et al. Front Neurol 2017;8:37
Microbial products → olfactory and/or enteric neurons → aggregation of α-synuclein
Dual-hit hypothesis: • Sporadic PD starts in the
neurons of the nasal cavity
and the neurons in the gut
100 trillion bacteria (5 lbs)
2/3 specific to each individual
Microbiota dysbiosis in PD• High prevalence of
Helicobacter pylori in PD(eradication does not improve outcome)
• Significant reduction of
Lachnospiraceae in stools of
PD patients compared to HC
Barichella et al. Mov Disord 2019;
34:396-405
Scoop on Poop in Parkinson’s disease
Erny D, Prinz M. Nature 2017;544:304-5
Sampson et al. Cell 2016;167:1469–80
SCFA = short-chain fatty acids
Neuron DOI: (10.1016/j.neuron.2019.05.035) Kim et al (Dawson). Neuron 2019;103:1-15
Transneuronal Propagation of Pathologic α-Synuclein
from the Gut to the Brain Models Parkinson’s Disease
• Gut injection of α-
synuclein fibrils converts
endogenous α-synuclein
to a pathologic species
that spreads to the brain →
PD
• Vagotomy and α-synuclein
deficiency prevent the
neuropathology and
neurobehavioral deficits
induced by transmitted
pathological α-synuclein.
• PD-like pathology and
symptoms require
endogenous α-synuclein
• This study supports the
Braak hypothesis
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Parkinson’s disease: Neuropathology
Braak’s Hypothesis
Poewe et al. Nat Rev Dis Primers 2017;3:17013
Braak’s HypothesisCriticism
• Initial cases preselected on the basis of Lewy body pathology (LP) in DMV
• Staging is based on LP rather than neuronal loss
• Not all patients follow the specific pattern; staging describes only young onset and long-duration of disease
• Up to a third of patients do not show LP in the ENS and may not show any pathology in the olfactory system (or in DMV despite LP in SN), thus challenging the dual-hit hypothesis
• Braak’s hypothesis does not explain early involvement of cardiac sympathetic nervesRietdijk et al. Front Neurol 2017;8:37
Alternative hypotheses – proteinaggregation is epiphenomenaEspay et al. Neurology 2019;92:329-37
α-synuclein toxicity in neurodegeneration: Mechanism and therapeutic strategies.
Wong YC, Krainc D. Nat Med 2017;23:1-13
Passive immunization
Jankovic et al. JAMA Neurol 2018;75:1206-14
Mov Disord 2019;34:41-4
PRX002/RG7935
Prasinezumab
Aggregated,
extracellular
α-synuclein
Synuclein immunotherapy may reduce neuronal toxicity
and prevent cell-to-cell transfer
Savitt D, Jankovic J. Targeting α-Synuclein in Parkinson's Disease.
Drugs 2019;79:797-810
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Detection of α-synuclein
Zerr. Lancet Neurol 2021;20:165-6
In-vitro misfolded protein amplification systems, such as protein
misfolding cyclic amplification (PMCA) and real-time quaking-
induced conversion (RT-QuIC) assays facilitate the diagnosis of
neurodegenerative diseases.
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Both immunofluorescence and (≥) RT-QuIC showed high diagnostic accuracy, supporting the use of skin immunofluorescence or RT-QuIC
instead of CSF RT-QuIC as a diagnostic tool for synucleinopathies.
RT-QuIC assay(A) Synucleinopathies (n = 31),
non-synucleinopathies (n = 38),
and controls (n = 24)
(B) Synucleinopathies (n = 9), non-
synucleinopathies (n = 24),
and controls (n = 16)
Real-Time Quaking-Induced Conversion (RT-QuIC) Assay of Skin and CSF Samples From PD Patients
Donadio et al. Neurology 2021;96:e2513-e2524
skin CSF
SYNTap™ Biomarker Test
1-858-461-6338 (San Diego, CA)
• This α-synuclein seed aggregation assay (SAA) was granted
Breakthrough Device Designation by the US FDA for detecting
misfolded aggregates of α-synuclein in patients who are undergoing
evaluation for PD.
• The CSF test is used as a predictive tool to aid in diagnosis of
synucleinopathies with overall accuracy compared to clinical
diagnosis (PD, LBD) of 83.9%, sensitivity 78.7%, specificity 89.5%.
• Results are reported as “Detected”, “Not Detected” or “Indeterminate”
(Amprion does not bill the patient for indeterminate test results).
• Official lab report available within 15 business days of receiving a CSF
sample. Cost: $1500.
Kang et al. Mov Disord 2019;34:536-44
Shahnawaz et al. JAMA Neurol 2017;74:163-72
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Genetically-Determined Parkinsonism
Disease Inher.Gene Locus
(Gene)Protein
PARK-SNCA (PARK1) – typical PD AD4q21-23 (SNCA)A53T; A53E; A30P;
E46K; H50Q; G51D
α-synuclein
PARK-Parkin (PARK2) – early-onset, dystonia
AR6q25.2-27(PRKN, Parkin)
Ubiquitin ligase
PARK3 – typical PD AD 2p13 Unknown
PARK4 – parkinsonism, dementia, dysautonomia, postural tremor, LB, GCI
AD 4q21 α-synuclein triplication
PARK5 – PD AD4p14(UCH-L1)
Ubiquitin cyclohydrolase A
PARK-PINK1 (PARK6) – early-onset AR1p36(PINK1)
PTEN-induced kinase 1
PARK-DJ-1 (PARK7) – early-onset AR1p36(DJ-1)
DJ-1
PARK-LRRK2 (PARK8) – PD AD12p11.23-q13.11(LRRK2)
LARRK2 (Dardarin)
PARK-ATP13A2 (PARK9) (Kufor-Rakebsyndrome) – early-onset, levodopa-responsive, spasticity, dementia, ophthalmoparesis, pallidal atrophy, T2-striatal hypointensity
AR1p36
(ATP13A2)
Lysosomal type 5 P-type ATPase
Deng H, Wang P, Jankovic J. Ageing Res Rev 2018;42:72-85Marras et al. Mov Disord 2016;31:436-57
McNaught et al. Nat Rev Neurosci 2001;2:589-94
Impairments in degradation of abnormal proteins by the ubiquitin–proteasome system lead to the development of
Parkinson's disease
Parkin
PARK2 (PRKN mutations)
• Compound heterozygotes for PRKN account for nearly 50% of patients with early onset PD
• May present with dystonic gait, cervical dystonia, dopa-responsive dystonia
• Usually symmetrical, but may also present as hemiparkinsonism-hemiatrophy
• Freezing, festination, retropulsion
• Leg tremor at rest and on standing
• Marked sleep benefit
• Hyperreflexia
• Ataxia
• Peripheral neuropathy
• Dysautonomia
• Levodopa-responsive; early levodopa-induced dyskinesias, hallucinations, high frequency of ICD
• Pathology: Loss of SNpc neurons, but dorsal tier is preserved; mild neuronal loss in LC and DMN-X, but not in NB-Meynert, raphe nucleus, or other brain regions; rare LBs
Compound Heterozygous PRKN Mutation
Deng et al. Arch Neurol 2006;63:273-7
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Genetically-Determined Parkinsonism
Disease Inher.Gene Locus
(Gene)Protein
PARK-SNCA (PARK1) – typical PD AD4q21-23 (SNCA)A53T; A53E; A30P;
E46K; H50Q; G51D
α-synuclein
PARK-Parkin (PARK2) – early-onset, dystonia
AR6q25.2-27(PRKN, Parkin)
Ubiquitin ligase
PARK3 – typical PD AD 2p13 Unknown
PARK4 – parkinsonism, dementia, dysautonomia, postural tremor, LB, GCI
AD 4q21 α-synuclein triplication
PARK5 – PD AD4p14(UCH-L1)
Ubiquitin cyclohydrolase A
PARK-PINK1 (PARK6) – early-onset AR1p36(PINK1)
PTEN-induced kinase 1
PARK-DJ-1 (PARK7) – early-onset AR1p36(DJ-1)
DJ-1
PARK-LRRK2 (PARK8) – PD AD12p11.23-q13.11(LRRK2)
LARRK2 (Dardarin)
PARK-ATP13A2 (PARK9) (Kufor-Rakebsyndrome) – early-onset, levodopa-responsive, spasticity, dementia, ophthalmoparesis, pallidal atrophy, T2-striatal hypointensity
AR1p36
(ATP13A2)
Lysosomal type 5 P-type ATPase
Deng H, Wang P, Jankovic J. Ageing Res Rev 2018;42:72-85Marras et al. Mov Disord 2016;31:436-57
PINK1-associated Parkinson’s Disease
• PINK1, protein kinase, accumulates on the outer membrane of
damaged mitochondria, phosphorylates (activates) Parkin's E3
ubiquitin ligase, and recruits Parkin to the dysfunctional
mitochondrion
• Specific PINK1 mutation (p.G411S) decreases the activity, but not
the protein level, of wild-type PINK1 in a dominant-negative fashion
• AR (biallelic mutations) parkinsonism with mean age at onset
around 40 years, may be associated with pyramidal signs and
hyperreflexia
• Slow progression, PIGD, dystonia, sleep benefit
• Levodopa-responsive, may require DBS for motor fluctuations and
dyskinesia
• Depigmentation of SNpc, SN gliosis, Lewy-body and synuclein
pathology
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DJ1-associated Parkinson’s Disease
• The oncogene DJ1 protects against damage from oxidative stress
and may act in a parallel pathway to that of parkin and PINK1
• Mutations in DJ1 were first described in consanguineous European
families
• 1-2% of early-onset PD cases with median age at onset at 30 years;
juvenile onset in 13%
• Clinical and neuroimaging features of PARK-DJ1 are similar to
PARK-parkin and PARK-PINK1, but non-motor symptoms have
been reported considerably more frequently in PARK-DJ1 (57%)
compared to PARK-parkin (13%) and PARK-PINK1 (42%)
• Neuron loss in the SNpc and LC, and widespread LB pathology;
alpha synuclein deposition in skin
• MRI is usually normal and dopaminergic imaging is abnormal in
PARK-DJ1, similar to PARK-parkin and –PINK1
Mitochondrial Dysfunction in PD
• PRKN, PINK1, DJ-1 mutations → loss of mitochondrial function
• Parkin normally promotes autophagy of damaged mitochondria;
failure to eliminate dysfunctional mitochondria leads to cell death
• 30 to 40% decrease in complex I activity in SNpc in PD
(no loss in MSA or PSP)
• Axonal mitochondria regulate bioenergetic metabolism, reactive
oxygen species (oxidative stress), Ca2+ homeostasis, etc
• Axonal mitochondria are particularly vulnerable and their
dysfunction can contribute to impaired axonal transport
• Distal axons may be the initial site of neurodegeneration in PD
Neuronal vulnerability in Parkinson disease: Should the focus be on axons and synaptic terminals?
Wong et al. Mov Disord 2019;34:1406-22
Loss of dopamine neurons in the SNc
and dopamine terminals in the striatum
drive the motor features of PD.
Extensive axonal arborization in the
striatum imposes extraordinary
metabolic costs with increased
energetic demands on striatal
mitochondria, oxidant stress, protein
delivery, and proteasomal systems.
PD is an axonopathy
Tagliaferro P, Burke RE. J Parkinsons Dis 2016;6:1-15Padmanabhan S, Burke RE. Mov Disord2018;33:62-70O'Keeffe GW, Sullivan AM. Parkinsonism Relat Disord 2018;56:9-15
Implication of mitochondrial dysfunction in the pathobiology of Parkinson’s disease
• PINK1, protein kinase,
accumulates on the outer
membrane of damaged
mitochondria,
phosphorylates (activates)
Parkin E3 ubiquitin ligase,
and recruits Parkin to the
dysfunctional mitochondrion
• During oxidative stress
cytoplasmic tyrosine kinase
Abelson (cAbl) moves to
mitochondria and promotes
accumulation of misfolded
proteins
• c-Abl kinase inhibitors tested
in early PD
Gaki GS, Papavassiliou AG. Neuromolecular Med 2014;16:217-30
PARL= presenilin-associated rhomboid-like serine protease
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Genetically-Determined Parkinsonism
Disease Inher.Gene Locus
(Gene)Protein
PARK-SNCA (PARK1) – typical PD AD4q21-23 (SNCA)A53T; A53E; A30P;
E46K; H50Q; G51D
α-synuclein
PARK-Parkin (PARK2) – early-onset, dystonia
AR6q25.2-27(PRKN, Parkin)
Ubiquitin ligase
PARK3 – typical PD AD 2p13 Unknown
PARK4 – parkinsonism, dementia, dysautonomia, postural tremor, LB, GCI
AD 4q21 α-synuclein triplication
PARK5 – PD AD4p14(UCH-L1)
Ubiquitin cyclohydrolase A
PARK-PINK1 (PARK6) – early-onset AR1p36(PINK1)
PTEN-induced kinase 1
PARK-DJ-1 (PARK7) – early-onset AR1p36(DJ-1)
DJ-1
PARK-LRRK2 (PARK8) – PD AD12p11.23-q13.11(LRRK2)
LARRK2 (Dardarin)
PARK-ATP13A2 (PARK9) (Kufor-Rakebsyndrome) – early-onset, levodopa-responsive, spasticity, dementia, ophthalmoparesis, pallidal atrophy, T2-striatal hypointensity
AR1p36
(ATP13A2)
Lysosomal type 5 P-type ATPase
Deng H, Wang P, Jankovic J. Ageing Res Rev 2018;42:72-85Marras et al. Mov Disord 2016;31:436-57
• Large protein (2527 AAs), also referred to as “dardarin” (tremor)
• LRRK2 is involved in vesicular trafficking, autophagy, protein
synthesis, and cytoskeletal function; it also interacts with
mitochondrial proteins and may be involved in immune system
• LRRK2 is highly expressed in the medium-sized spiny neurons of the
striatum; also in macrophages and microglia suggesting an
involvement in inflammatory pathways
• LRRK2 is also highly expressed in kidney, lung, and peripheral
immune cells
• Hundreds of mutations in LRRK2 associated with PD but only few are
pathogenic
• LRRK2 mutations result in gain-of-function, with increased GTPase
and kinase activity (both phosphorylation and autophosphorylation)
• LRRK2 gain-of-function mutations increase life-time risk for PD 20-fold
(also increase risk for Crohn’s disease)
LRRK2(Leucine Rich Repeat Kinase 2) Structure and function of LRRK2
Tolosa et al. Nat Rev Neurol 2020;16:97-107
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LRRK2
Rideout et al. Front Neurosci 2020;14:865
• LRRK2 mutations account for 1-2% of sporadic cases and 5% of familial PD in the US
• G2019S mutation accounts for up to 10% of all “sporadic” PD and 42% of familial cases in Europe and North Africa, particularly North African Berbers, Iberian populations, and in Ashkenazi Jews (13% of sporadic, 30% of familial cases)
• Penetrance 26-100%
LRRK2(Leucine Rich Repeat Kinase 2)
Trinh et al. JAMA Neurol 2014;71:1535-9
LRRK2 variants may also
increase the risk of sporadic PD
Di Maio et al (Greenamyre). Sci
Transl Med 2018; 10(451):
eaar5429
Monfrini E, Di Fonzo A.
Adv Neurobiol 2017;14:3-30
Rideout et al. Front Neurosci
2020;14:865
• LRRK2 positive cases have slightly more benign course (although
more likely PIGD), have less RBD, and better olfaction than sporadic
idiopathic PD, M:F=50:50
• G2019S mutation carriers have milder motor symptoms than G2385R
mutation carriers, but both G2019S and G2385R mutation carriers had
a higher proportion of the PIGD phenotype compared with idiopathic
PD patients (Marras et al. Mov Disord 2016;31:1192-202)
• PPMI LRRK2 genetic mutations: G2019S>>R1441G/C>N1437H
(Simuni et al. Mov Disord 2020;35:833-44)
• Atypical features: orthostatic hypotension, dementia, hallucinations,
sleep disturbance, but olfaction may be relatively preserved; may also
have features of corticobasal syndrome, including primary progressive
aphasia
• Pathology is heterogeneous: may or not include Lewy bodies or
synuclein pathology; may overlap with MSA and DLB
(synucleinopathies), and with CBD and PSP (tauopathies)
LRRK2(Leucine Rich Repeat Kinase 2)
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Marras et al. Mov Disord 2016;31:436-57
Genetic Classification of Parkinsonism
GBA = Glucocerebrosidase
GBA Mutations in PD
Sidransky et al. N Engl J Med 2009;361:1651-61
• In AJ individuals with
PD, N370S is the most
common GBA mutation
• PPMI GBA mutations:
N370S, L483P, L444P,
IVS2 + 1, and 84GG
(Simuni et al. Mov Disord
2020)
• GBA mutations are more
common among PD
patients of AJ ancestry
GBA Mutations in PD
Sidransky et al. N Engl J Med 2009;361:1651-61
Clinical Manifestations
Compared to idiopathic PD, patients with GBA mutations tend to have earlier age at onset, are more likely to have affected relatives, cognitive deficit, and more severe depression, RBD, dysautonomia, and LID.
Glucocerebrosidase and Parkinsonism
• Glucocerebrosidase (GBA) gene, located on 1q21, encodes the
lysosomal enzyme glucocerebrosidase that decomposes
glucocerebroside into glucose and ceramide and plays an important
role in sphingolipid degradation.
• Gaucher’s disease, the most prevalent lysosomal storage disorder, is
due to homozygous GBA mutations leading to low glucocerebrosidase
enzymatic activity and accumulation of glucocerebroside in the spleen,
liver and bone marrow (hepatosplenomgaly).
• Neurological manifestations include parkinsonism, horizontal
supranuclear palsy, seizures, dementia, ataxia, and spasticity
• Homozygous or heterozygous GBA mutations confer 5-20 fold
increased risk of PD - GBA carriers have 30% risk of developing PD by
age 80 years
• 6% of AJ are carriers of GBA mutations; GBA mutations are found in
10% of sporadic PD and in >40% of familial AJ PD patients
– the most important risk factor for PD
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Glucocerebrosidase and Parkinsonism
• Impaired olfaction, cognitive impairment, and motor prodromal signs
(depression, RBD?) are more pronounced in GBA carriers
• Mutations or variants in one GBA allele are associated with earlier
onset, more rapid progression of parkinsonism and higher risk of
dementia and RBD compared to those without GBA mutations
Davis et al. JAMA Neurol 2016;73:1217-24; Cilia et al. Ann Neurol
2016;80:662-73
• Mild mutations: N37OS, E326; Severe mutations: L444P, 84GG
• Look for hepatosplenomegaly and elevated serum chitotriosidase
(normal: <150 nmol/hr/mL)
• Absent glucocerebrosidase activity in leukocytes
• CSF glucosylceramide to sphingomyelin (G/SM) ratio is increased in
GBA-PD; positively correlates with increasing mutation severity
• Postmortem studies of PD patients with GBA mutations show Lewy
bodies in cortical areas corresponding to Braak stages 5–6 in addition
to the classic PD pathology.
β-Glucocerebrosidase and Parkinsonism
• GBA-related PD is associated with low CSF total alpha-synuclein,
especially with severe mutations (e.g. L44P)
Lerche et al. Mov Disord 2020;35:495-9
• GBA homozygotes/compound heterozygotes have lower enzymatic
activity than GBA heterozygotes and higher glucocerebrosidase
enzymatic activity is associated with longer disease duration (a milder
disease course)
Alcalay et al. Brain 2015;138:2648-58
• β-glucocerebrosidase enzyme measured in blood inversely correlates
with clinical severity types of GBA mutations in PD
Longitudinal β-glucocerebrosidase activity in participants with different types of GBA mutationsHuh et al. Neurology 2020;95:e685-e696
Mutant glucocerebrosidase → α-synuclein aggregation
Sidransky E, Lopez G. Lancet Neurol 2012;11:986-98
α-syn has been implicated in the regulation of neuronal cholesterol, and cholesterol facilitates interactions between α-syn oligomers. Additionally, GCase and cholesterol play a role in LB pathology.
The Role of Cholesterol in α‐Synuclein and Lewy Body Pathology in GBA1 Parkinson's Disease
García-Sanz et al. Mov Disord 2021;36:1070-85
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The Emerging Role of the Lysosome in PD
Navarro-Romero et al. Cells 2020;9:E2399
Several of the genes
associated with PD as well
as several genetic risk
factors encode for
lysosomal, autophagic, and
endosomal proteins.
Mutations in these PD-
associated genes can cause
lysosomal dysfunction which
can affect α-synuclein
turnover.
Recent studies have also
highlighted the bidirectional
link between Parkinson's
disease and lysosomal
storage diseases (LSD).
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Genetic diagnosis in 19.3% of our familial PD cohort
https://www.parkinson.org/PDGENEration
Other genetic studies: MJFF-PPMI (LRRK2 – G2019S; GBA – N37OS)
NCBI Genetic Testing Registry
https://www.ncbi.nlm.nih.gov/gtr/
Specific genes: www.invitae; www.athenadiagnostics.com
WES: www.baylorgenetics.com; www.genedx.com
GBA, Lysosomal disorders: Greenwood Genetics Center
www.ggc.org; www.fulgentgenetics.com
Genetic Testing in Patients with Parkinsonism and Other Movement Disorders
Potential Pathogenic Mechanisms in Parkinson’ Disease
Deng H, Wang P, Jankovic J. Ageing Res Rev 2018;42:72–85
Who knew it was so complicated?
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Jankovic J, Tan EK. JNNP 2020;91:795-808
Genetic and Environmental Factors in PD Converge on Immune Function and Inflammation
Kline et al. Mov Disord 2021;36:25-36
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Nat Rev Neurol 2020;16:303-18
Mechanisms of microglial involvement in dopaminergic neuron damage.
Tan et al. Nat Rev Neurol 2020;16:303-18
Evidence for involvement of the immune system in Parkinson disease
Tan et al. Nat Rev Neurol 2020
Impaired meningeal lymphatic drainage in patients with idiopathic Parkinson's disease.
Ding et al. Nat Med 2021;27:411-8
• Animal studies implicate meningeal lymphatic dysfunction in the
pathogenesis of neurodegenerative diseases such as AD and PD.
• Using dynamic contrast-enhanced MRI patients with iPD were found
to exhibit significantly reduced flow through the meningeal
lymphatic vessels (mLVs) along the superior sagittal sinus and
sigmoid sinus, as well as a notable delay in deep cervical lymph
node perfusion, compared to patients with AP.
• In mice injected with α-synuclein (α-syn) preformed fibrils the α-syn
pathology was followed by delayed meningeal lymphatic drainage,
loss of tight junctions among meningeal lymphatic endothelial cells
and increased inflammation of the meninges.
• Blocking flow through the mLVs in mice treated with α-syn
preformed fibrils increased α-syn pathology and exacerbated motor
and memory deficits.
• These results suggest that meningeal lymphatic drainage
dysfunction aggravates α-syn pathology and contributes to the
progression of PD.
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Prion-like spread of protein aggregates and proposed role of glymphatic transport
Nedergaard M, Goldman SA. Science 2020;370:50-5
“Only the sleeping brain is capable of efficiently clearing the waste products generated during active wakefulness.”
www.jankovic.org
Parkinson’s Disease Center and Movement Disorders Clinic
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