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Amyotrophic LateralSclerosis

Authors: Vanessa Nowosad and GenevieveGo

Citations in APA Format

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+Introduction & istory

Amyotrophic lateral sclerosis !also "nown as Lou Gehri#$sdisease% is an adultonset' neurode#enerative disease with anun"nown cure(

) out o* +,,',,, people worldwide are a-ected .y ALS( +,/ o*cases o* ALS are the result o* a #enetic de*ect' while the othercases is are sporadic and the cause un"nown(

Pea" a#e onset is )0 to 12 years o* a#e !3iernarn et al(' 4,++%(

It consists o* death o* motor neurons in the .rain' .rainstemand spinal cord' which leads to the pro#ressive *ailure o* the

neuromuscular system and death within 42 years *romsymptom onset !Ferraiuolo et al(' 4,++%(

5here has .een evidence that ALS is neurovascular disease duedo the impairment o* .lood.rain and .loodspinal cord .arriers!66676SC6% !Gar.u8ova9avis et al(' 4,++%(

A% Introduction

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+6% istory

Au#ustus aco. Loc"hart Clar"e!+0+;+00,% made a maartin Charcot in +0;?(

@ver the past +), years' sinceCharcot$s ori#inal description'little has .een discovered a.outthe causes o* ALS(

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+Cause o* ALS

>utations in the S@9+' 5A96P' and *used in sarcoma#ene !FBS% have .een identied in *amilial ALS!3a.ashi et al(' 4,++%(

=vidence su##ests that ALS could initiate in s"eletalmuscle rather than in motor neurons !>arcu88o et al('4,++%(

Immunological causes are still .ein# studied' .utcurrent research proposes that ALS patients have

anti.odies that reco#ni8e various neuronal structuressuch as calcium receptors as *orei#n

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+ >echanisms

Glutamateinduced eDcitotoDicity results in the overactivation o*calcium dependent en8ymatic pathways as well as the#eneration o* superoDides !3iernan et al(' 4,++%(

@Didative stress plays a crucial role in the pro#ression o* motorneuron loss o.served in this disease !5ana"a et al(' 4,++%(

=ndoplasmic reticulum and mitochondrial stress *rom increasedECa4 activates the un*olded protein response !Hal"er & At"in'4,++%(

It is su##ested that these mechanisms are part o* a series orparallel events leadin# to neuronal death( An increase in ECa4could enhance the #eneration o* superoDides and the release o*#lutamate and in turn increase ECa4*urther !Pa#ani et al.'4,++%(

Increased intracellular ECa4' eDcitotoDicity mediated .y #lutamate'

and #eneration o* superoDides !Pa#ani' Gon8ale8' & Bchitel' 4,++%

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+Calcium inuD

I#G anti.odies have.een *ound a#ainstcalcium !Ca4%channels !Gon8ale8'et al(' 4,++%

Anti.odies reco#ni8echannel as *orei#n'.inds' allows *orinuD o* calcium'

calcium enters intomitochondria' causesstress' and si#nalsapoptosis

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+S@9+ mutations S@9+' super oDide dismutase +'

.inds to cooper and 8inc ions and

is responsi.le *or destroyin# superoDide radicals SuperoDides are produced .y the

immune system to destroy *orei#ncells

>is*oldin# o* mutated S@9+

!en"el et al(' 4,,J%

>icro#lia cells secreteinammatory mediators in the.rain >utant S@9+ GJ2Ais reco#ni8ed .y

micro#lia and is activated due to.indin# o* C9+? and 5L4 and 5L?

Activated phenotype !m+% promotes5h+ responses' secretesproinammatory cyto"ines !5NFK' IL+ and @S superoDide%' leadin# toapoptosis o* motor neuron cells

!Mhao et al(' 4,,J%

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+Symptoms & 9ia#nosis

People with ALS lose muscle stren#th and coordination(Symptoms include diculty swallowin# and .reathin#'wea" muscles' muscle cramps' muscle contractions'

paralysis' speech pro.lems' and wei#ht loss !Pu.>edealth' 4,+,%(

Co#nitive a.ilities such as personality chan#es'lan#ua#e and decision ma"in#' are impaired in 4)),/o* patients who receive neuropsycholo#ical tests

!Gordon' 4,++%(

A% Symptoms

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+6% 9ia#nosis

5here is no dia#nostic test *oramyotrophic lateral sclerosis' sophysicians must rely on identi*yin#.oth upper and lower motor neuronsi#ns in lim.s and other physicalevidence *or the pro#ression o* the

disease !3iernanet al.' 4,++%(

Nerve conduction studies areimportant *or reducin#misdia#nosis o* ALS' andelectromyo#raphy is essential *or

the identication o* lower motorneuron loss O this can help in theearly dia#nosis o* ALS !3iernanetal.' 4,++%(

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+Current 5reatments

6ecause there is no apparent cause in the maed ealth' 4,+,%(

Symptomatic treatments such as physiotherapy'speech therapy' and respiratory therapy help mana#e

the a-ects o* the disease !3iernanet al.' 4,++%(

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+Clinical esearch & 5rials

@Didative stress plays a lar#e role in the pro#ression o*motor neuron loss o.served in ALS' so antioDidativea#ents could .e an important therapeutic means *orthe ALS treatment antioDidant supplements !5ana"a'et al(,4,++%(

Identication o* .iomar"ers that inuence theoccurrence and pro#ression o* ALS' includin# #enesother than S@9+' is a prominent area o* research(

59P?2 #ene has more than 2, mutations in the Cterminus!a .indin# domain *or ri.onucleoproteins% that have .een

identied in .oth *amilial and sporadic ALS patientshowever' the mechanism is still un"nown !@nodera et al('4,++%

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+Conclusion & Future Studies

5he underlyin# mechanisms that induce the #eneration o*autoanti.odies that reco#ni8e calcium channels are stillnot "nown(

5he identication o* more anti#enic tar#ets will provide away to determine the precise role o* autoimmunity in thisdisease(

Screenin# to identi*y the molecular tar#ets *or anti.odies*rom ALS patients is necessary desi#n rational therapiesand to develop .iochemical tests *or early detection o*

ALS(

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+e*erences

QAmyotrophic Lateral Sclerosis Pu.>ed ealth(QAmyotrophic Lateral Sclerosis( NationalCenter *or 6iotechnolo#y In*ormation' B(S( National Li.rary o* >edicine' 4;

Au#( 4,+,( He.( +; Nov( 4,++(Rhttp:77www(nc.i(nlm(nih(#ov7pu.medhealth7P>,,,+;,07(

Ferraiuolo' L(' i##in.ottom' A(' eath' P( (' 6ar.er' S(' Greenald' 9(' 3ir.y' (' & Shaw' P(( !4,++%( 9ysre#ulation o* astrocyteOmotoneuron crosstal" in mutantsuperoDide dismutase +related amyotrophic lateral sclerosis( Brain: A JournalOfNeurology' 134!J%' 414;41?+(

Gar.u8ova9avis' S(' odri#ues' >( @(' ernande8@ntiveros' 9( G(' Louis' >( 3(' Hillin#'

A( =(' 6orlon#an' C( V(' & San.er#' P( ( !4,++%( Amyotrophic lateral sclerosis: Aneurovascular disease( Brain esearch' 13!"++2+4)( doi:+,(+,+17ulat8' 3( (' Snutch' 5(P(' Bchital' @( 9( !4,++%( Amyotrophic lateral sclerosisimmuno#lo.ulinsselectively interact with neuromuscular

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+3iernan' >(' Vucic' S(' Cheah' 6(' 5urner' >(' =isen' A(' ardiman' @(' & ((( Moin#' >(!4,++%( Amyotrophic lateral sclerosis( Lancet' 3))!J;1J%' J?4J))(

>arcu88o' S(' Mucca' I(' >astropietro' A(' de os.o' N(' Cavalcante' P(' 5artari' S(' 6onanno'S(' Preite' L(' >ante#a88a' (' & 6ernasconi' P( !4,++%( ind lim. muscle atrophy

precedes cere.ral neuronal de#eneration in GJ2AS@9+ mouse model o*amyotrophic lateral sclerosis: A lon#itudinal >I study( *+perimental Neurology'31!+%' 2,2;( doi:+,(+,+17(' Swash' >(' & =.ers' G( !4,+,%( Loc"hart Clar"es contri.ution to thedescription o* amyotrophic lateral sclerosis( Brain: A Journal Of Neurology'

133!++%' 2?;,2?;J(

Hal"er' A( 3(' & At"in' ( 9( !4,++%( Stress si#nalin# *rom the endoplasmic reticulum: Acentral player in the patho#enesis o* amyotrophic lateral sclerosis( IB6>6 Li*e' 12!J%';)? ;12( doi:+,(+,,47iu.()4,

Mhao' H(' 6eers' (' en"el' (' Mhan#' H(' Brushitani' >(' ulien' (' & Appel' S(Q=Dtracellular >utant S@9+ Induces >icro#lialmediated >otoneuron InC4;0?+107http:77(