Lysosomal storage disease.ppt

8/20/2019 Lysosomal storage disease.ppt

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Lysosomal Storage Disease

Module 755

The Brain in Health and Disease

Sean Sweeney


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Lysosomal Storage Disease (Amaurotic Idiocy)

c.a. 45 autosomal recessive diseases

Individually rare

Collectively occur c.a. 1/8 live !irt"s

Cause deat" in early to late c"ild"ood (a#ter normal in#ancy)

$arying involvement o# t"e nervous system

All %store& material in t"e lysosome due to de#ects insu!strate degradation or !iogenesis o# t"e lysosome


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'"e Lysosome

su!cellular electron dense organelle

#illed it" c.a. "ydrolytic en*ymes+ ill !rea, don all!iological macromolecules

lo - (4.)0 mem!rane !ound

Considered t"e %gut& or gar!age dis-osal unit o# cell

aterial #or degradation tra##ic,ed to lysosome via endocytosisor auto-"agy

Lysosomal en*ymes tra##ic,ed to lysosome via 23 rece-tor -at"ay


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ndosome to lysosome+decreasing -0 mem!ranelimited.

Autophagy: controls cell si*e0used during caloric restriction0Phagocytosis: degrades%dead& cells0 -at"ogens

Auto-"agy and -"agocytosismeet in t"e PhagolysosomePro!essional Phagocytes:

macro-"ages0 neutro-"ils

Delivering material #ordegradation to t"e lysosome+endocytosis and auto-"agy


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ndocytosis in t"e nervous system

QuickTime™ and a TIFF (Uncompressed) decompressor

are needed to see this picture.

'"e -olarised and etendedstructure o# t"e neuron creates

a tra##ic,ing -ro!lem #or neurons+

%lysosomes& (as e ,no t"em6)not -resent at syna-se.

Late endosomal mar,ers -resent+#use it" lysosomes in t"e soma


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Delivering degradative en*ymes and co7#actors to t"e lysosome0 t"e 23/23-at"ay.

annose727-"os-"ate grou- added to lysosomal"ydrolases via 97lin,ed oligosacc"arides as"ydrolases transit t"roug" cis7golgi

23 recognised !y 237rece-tors in trans7golgi+delivers t"em to late endosome

Loer - causes dissociation

23 t"en retrieved in late endosomeand tra##ic,ed #or re7use in trans7golgi(recognised via C7terminal tail).


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:eneral outline o# LSD dys#unction+

utations arising in "ydrolytic en*yme0 co7#actor or

#actor essential o# en*yme delivery to lysosome

Also0 #actors essential #or lysosome #unction and!iogenesis (mem!rane -roteins0 c"annels and -roteins o#

un,non #unction) -lus #actors #or -rotein tra##ic to lysosome

aterial (su!strate) continues to !e delivered to lysosomeresulting in %stored& material0 usually %-rimary& and %secondary&leads to sollen lysosomes

Develo-mental dys#unction and early deat"+ sym-tomsv. varia!le0 varying involvement o# di##erent tissues


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:eneral Cellular 3"enoty-e+

Sollen0 multilammellar %osmio-"ilic endosomes/lysosomes(#unction; -;)

Accumulation o# li-o#uscin/ceroid %ageing -igment&

De#ects in auto-"agy (;)

A--earance o# meganeurites (varia!le)




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Cellular -"enoty-e contd.

cessive syna-togenesis/dendritogenesis(3S and s-"ingoli-idoses)

S"rin,age o# t"e C9S (varia!le)

istra##ic,ing o# c"olesterol(c"olesterol recycling;)


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Classi#ication +

uco-olysacc"aridoses (varia!le nervous system involvement)

ucoli-idoses (originally considered an 3S):lyco-roteinoses:lycogen storageS-"ingoli-idoses

Li-id storage disordersulti-le en*yme de#ects'rans-ort de#ects=atten Disease

(ed > nervous system involvement)


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Mucopolysaccharides

? Defective metabolism and accumulation of GAGs? Most abundant polysaccharides? Long unbranchedstructure containing disaccharide units:? High viscosity + rigidity? Excellent lubricators and shock absorbers? Important component of cell membranes


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uco-olysacc"aridoses+ n*yme De#ective

3S7I+ (urler0 S"eie0 urler/S"eie) iduronidase

3S7II+ (unter) iduronate7@7sul#atase3S7III+ (San#ili--o)

IIIA "e-aran797sul#ataseIII= 97acetyl7glucosaminidase

IIIC Acetyl Co7A glucosamine97acetyl trans#erase

IIID 97acetyl7glucosamine727sul#atase3S7I$ (oruio)

I$A 97acetyl7galactosamine 27sul#ataseI$= B7galactosidase

3S7$I (aroteau Lamy) 97acetyl7galatosamine 47sul#atase3S7$II (Sly) B7glucuronidase3S7I "yaluronidase


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San#ili--o Syndrome (3S III)

our ty-es+ A0=0C0D0 cannot !rea, don e-aran sul#ate

ost common 3S0 1/0 !irt"s

"e-atos-lenomegaly (may resume normal si*e it" age)y-eractivityS-eec" delayental retardationEoint sti##ness0 !one de#ects (dystosis multi-le)Coarse #eatures (dysmor-"ismDeat" in middle teens

Screening+ :A:s in urineDiagnostic+


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ucoli-idosis (I7Cell disease) and 3S7I$

ucoli-idosis7III7Cell (3seudo7urler)+ #irst descri!ed 1F2I > "nclusion0 stored material mucoli-id 3S and s-"ingoli-idGccurrence+ 1/240 live !irt"sSym-toms+ Develo-mental delay0 -syc"omotor deterioration0 dysmor-"ia0 deat" in

early c"ild"ood

:enetic de#ect+ 97acetylglucosaminyl717-"os-"otrans#erase

3rognosis+ v. -oor0 limited treatment (nutritional)0 deat" !y 1 years o# age.

ucoli-idosis7I$

Storage material+ mucoli-ids0 3S and s-"ingoli-idsGccurrence+ carriers in As",ena*im Eeis" -o-ulation0 1/F to 1/1Sym-toms+ 3syc"omotor retardation0 corneal o-acity0 retinal degeneration0 iron

de#iciency0 im-ro-er stomac" - (ac"loridia)

:enetic de#ect+ ucoli-in71 (CGL91)0 a '3 c"annel ('3L71)Involved in e@H e##lu #rom lysosomes; (Dong et al.0 (@8) 9ature0 4550 FF@72)

3rognosis+ v. -oor. 9utritional su--lements0 -"yscial and s-eec" t"era-y


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Sphingolipids: a ma#or component o! neural tissue

G

G

9

C@G

G

G

9

C@G 3 G (C@)@ 9H

G

G7

C

C

C

G

G

9

C@G :lcn

$eramide

Sphingomyelin

%lycosphingolipids

ST&'$T'&(

microdomains (;)tra##ic,ing

S"%)ALL")%

A-o-tosis-roli#erationstress

7 S-"ingomyelin

7 Ceramide 7 S-"ingosine 7 S-"ingosine717-"os-"ate 7 Cere!rosides 7 :angliosides


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S-"ingoli-ids aretig"tly associated it"c"olesterol


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'"e s-"ingoli-idoses+ 'ay7Sac"s (:@7gangliosidosis)

irst descri!ed in 188&s #rom %c"erry7red& s-ot in #undus (retina) (li-id de-osition in !i-olar ganglion cells)

In#antile (deat" 5yrs)0 Euvenile (deat" !eteen 5 and 15yrs) and %Late7onset& #orms (v. rare) All -resent it" increasing neurological and deterioration (ataia0 atro-"y0 s-asticity)

Gccurrence+ 1/@ to 1/ As",ena*im Ees are carriers0 also+ Acadians0 CaJuns

:enetic de#ect+ eosaminidase A (A)

storage material+ :@ ganglioside0 glo!oside0 glycoli-ids

c#+ Sand"o## Disease+ = mutations and :@ gangliosidosis(mutations in :@ activator -rotein)

:lial Involvement6

3rognosis+ early deat"0 ameliorated !y treatment

n*yme e-lacement '"era-ySu!strate eduction '"era-y

3o-ulation Screening

(model o# genetic screening #or recessive condition)




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Gt"er cellular de#ects+

9iemann73ic, disease+

occurrence+ A0 = collectively7 1/1 As",ena*im Ees are carriers0 ty-e C no et"nic distri!utionty-e A accounts #or 85K o# cases

Sym-toms+ enlarged s-leen and liver0 enlarged lym-" nodes0 dar,ening o# s,in0 neurologicim-airment (not in =)0 c"erry red s-ot

genetic de#ect+ A and =0 mutant #or s-"ingomyelinase'y-e C mutants+ to loci0 to -roteins0 multi7transmem!rane -rotein (related to

"edge"og rece-tor %-atc"ed& and small co7-rotein(c"olesterol !inding -rotein/carrier;).omolog 93CL1 involved in c"olesterol a!sor-tion in gut.

storage material+ s-"ingomyelin0 c"olesterol and s-"ingoli-ids

Diagnosis+ %#ili-in& staining

cell !iology (and diagnosis)+ mislocalised unesteri#ied c"olesterol0 neuro#i!rillary tangles

ndosomal tra##ic,ing Jam; c"olesterol and s-"ingoli-ids reuired to organise endosomaltra##ic,ing ste-s. C"olesterol recycled #rom lysosome.

Droso-"ila models reveal c"olesterol is %limited&


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=atten disease

A #amily o# closely related disorders

F #orms+ congenital0 in#antile0 late in#antile0 Juvenileadult

AA+ 9euronal Ceroid Li-o#uscinosis (9CL)

Incidence+ glo!al it" "ots-ots #or some loci

Loci+ %CL9& genes CL910 CL9@0 CL90 CL950 CL920 CL98 C'SDcloned so #ar0 ot"ers remain to !e ma--ed.

occurrence+ most common c"ild"ood neurodegeneration 1/8 live!irt"s

Sym-toms+ visual de#ects0 sei*ures0 stum!ling0 ec"olalia0 eventual loss o# sig"t s-eec"and motor s,ills0 early deat" a#ter !lindness0 dementia.

storage material+ Li-o#uscin/ceroid0 su!unit C o# mitoc"ondrial A'3 synt"ase

3"enoty-e+ multilamellar inclusions0 selective !rain cell deat" (glia mediated)in#iltration o# neuronal tissue it" anti!odies (de#ective ===;)

3rognosis and treatment+ anti7convulsives0 t"era-y. Deat" in c"ild"ood

=atten (1F)

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Locus Disease 3rotein de#iciency unction

CL91 in#antile 9CL -almitoyl -rotein t"ioesterase de7-almitoylationLysosome

CL9@ late in#antile 9CL tri-e-tidyl -e-tidase -roteaselysosome

CL9 Juvenile 9CL transmem!rane -rotein ;lysosome

CL94 adult (u#&s) 9ot identi#ied

CL95 late in#antile 9CL transmem!rane -rotein ;(innis" variant) L/lysosome

CL92 late in#antile variant transmem!rane -rotein -rotein

CL9 late in#antile variant 9ot Identi#ied

CL98 3 transmem!rane -rotein 0 /:olgi

C'SD Gvine 9CL cat"e-sin D -roteaselysosome


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ndocytosis in t"e nervous system



Lysosomes ("ydrolases6)not -resent at syna-se

any o# 9CL -roteins #oundat syna-se

93C -rotein0 ot"ers;

Identi#ication o# -roteins involved

in neurodegeneration "el-to descri!e #unctions in t"eneuron


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'reatment+=' (mem!rane -roteins)

en*yme re-lacement (===;)

gene t"era-y

su!strate reduction7 iglustat (monosacc"aridemimetic7imino sugar)

9euronal stem cells (mem!rane -roteins;)

C"emical c"a-erone t"era-y

9euroin#lammation


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conomic cost

' is current most e##ective treatment (non neurodegenerative LSDs)+

Disease 'reatment Annual Cost (-er -atient in M)

:auc"er ' 1450 7 @F0

:auc"er S' F10

a!ry ' 1520

urler7Sc"eie (3S7I) ' 40

aroteau7Lamy (3S7$I) ' 0

easons+ig" regulatory costsCost o# researc"Lac, o# com-etition (Gr-"an Drug Act 1F80 NS)


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Studying t"e Lysosomal Storage Diseases+

odel Grganisms

S"ee- (=atten)s"ee-dogs (=atten)mouse (=atten0 'ay7Sac"s0 Sand"o##0 93C)*e!ra#is" (=atten)Droso-"ila (3S0 93C0 =atten0 ot"ers)

C. elegans (3S0 93C)Oeast (cerviseae0 -om!e) =atten0 93C

everse :enetics (v 'ay7Sac"s)

orard :enetics


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"tt-+//1@[email protected]@.18/#ruit#ly/s"a,er/-"ysiology/

The Drosophila neuromuscular #unction:

A model glutamatergic synapse


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spinster synapses are overgrown

spinster

su--ressessyna-tic grot"

spinster mutants"ave a s"ortenedli#es-an


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spinster encodes a twelve transmembrane transporter

4 transcripts = 12 TM domains1 transcript = 8 TM domains


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Spin localises to a low pH late-endosomal compartment


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A low pH compartment is expanded inspin mutants


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WT spin4 /spin5

Loss of spinster induces a redistribution of cholesterol

filipin


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spinster identi#ies a novel com-onent o# t"e late endosome/lysosome t"at "en mutated givesrise to all o# t"e "allmar,s o# lysosomal storage diseasespinster -otentially identi#ies a signalling -at"ay driving syna-tic overgrot"


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Summary

Lysosomal storage disease are caused !y de#ects in lysosomal "ydrolases and -roteins

essential to lysosomal !iogenesis/#unction

LSD lysosomal de#ects give rise to sollen lysosomes0 develo-mental and degenerativede#ects it" varying involvement o# t"e nervous system due to %storage& o# materialin t"e lysosome.

Lysosomal storage diseases identi#y -roteins essential to lysosomal #unction

LSDs cause deat" in c"ild"ood (generally) a#ter normal in#ancy

LSDs are essentially incura!le0 !ut some are treata!le to varying degrees.

odel organisms are "el-ing to de#ine t"e !iology o# t"e LSDs0 in -articular t"e%-at"ogenic cascade&

Lysosomal storage disease.ppt

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