Amyotrophiclateralsclerosis(ALS)isaprogressiveneurodegenerativediseaseresultingfromlossofboth upperandlowermotorneuronsinthebrainandspinalcord.ALSsymptomsincludediffusemuscleweakness, muscleatrophy,spasticityandhyperreflexia(upper),paralysis(lower),and2-5yearlifeexpectancy.One approachtocombatALSisdeliveryofneurotrophicfactorstoprotectdamagedmotorneurons,butthisis dependentuponexpressionandpropersubcellularlocalizationofkeyneurotrophinreceptors.Neurotrophin receptoractivityisdependentuponlocalizationtospecializedmembranemicrodomainstermed membrane/lipidrafts(MLR).Ourgrouphasshownthatcaveolin-1(Cav-1),anMLR-scaffoldingprotein,is neuroprotective,increasesMLR-localizationofneurotrophinreceptors,andenhancesmitochondrialhealthand adaptationtostress.Moreover,invivodeliveryofneuron-targetedCav-1(usinganeuron-specificsynapsin promoter[SynCav1])increasesMLRformationandneurotrophinreceptor(e.g.,TrkB)localizationtoMLR, enhancesneuroplasticity,andsignificantlyimprovesbehavior.Forproof-of-conceptexperiments,wegenerated asynapsin-drivenCav-1overexpressingmouse(SynCav1TG)andcrosseditwithamousethatcontainsthe humanmutantsuperoxidedismutase1(hSOD1G93A)thatislinkedtoALS.WhencomparedtohSOD1G93A, hSOD1G93A/SynCav1+micedemonstratedpreservedbodyweightandlongersurvival,greatermotorevoked potentials(i.e.,greateramplitudeandlowerlatency),betterrunningwheelperformance,andmore?motor neuronsinthethoracicandlumbarvertebralcolumn.Furthermore,micehadmoreMLRandMLR-associated TrkBinspinalcordtissue.PreliminarydatashowthatsubpialspinalcorddeliveryofAAV9-SynCav1to hSOD1G93AratsimprovesMEPfunctionandforelimbgripstrength,whichsuggeststhatSynCav1maybeused asanoveltherapeuticinterventiontoreverseneurodegenerativediseasessuchasALS.Ouroverarching hypothesisisthatSynCav1genedeliveryinvivoaloneorincombinationwithaTrkBagonistwill improvemotorfunctionandextendsurvivalinaSOD1G93AmousemodelofALS.TheNewParadigmthat thisprojectintroducesliesintheapproachofusingasinglegeneticintervention,SynCav1to1)re-establisha polarizedmembranesignalingplatform,2)augmentneurotrophinsignaling,3)enhanceneuroplasticity,and4) extendsurvivalinthesettingofALS.Ourstudyrepresentsmorethananincrementaladvancementinthatit willuseanovelgenetherapyinterventioncombinedwithspecificreceptor-targetedpharmacologytorestore andaugmentpro-growthsignaling,axonalanddendriticgrowth,andformationofnewly,functionalsynapsesin thespinalcordofALSmodels.Theproposedresearchwillattempttouseanovelgeneticapproachto harnessthebody?snaturalpotentialforneuroplasticityandneuroregeneration.Byover-expressingCav-1 specificallyinCNSmotorneuronscombinedwithneurotrophicreceptoragonism,ourultimatelong-termgoalis toimproveneuromuscularfunctionandprolongsurvivalinVeteransafflictedALS.Assuch,theresearchhas directclinicalrelevancetothelong-termhealthofourVeterans.
Amyotrophiclateralsclerosis(ALS),knowncolloquiallyintheUnitedStatesas?LouGehrig?sdisease,?isa progressiveneurodegenerativediseaseresultingfromlossofbothupperandlowermotorneuronsinthebrain, brainstem,andspinalcord.ALSsymptomsincludediffusemuscleweakness,muscleatrophy,spasticity, hyperreflexia(upper),andparalysis(lower),accompaniedbya2-5yearlifeexpectancy.Theproposed researchwillattempttouseanovelapproachtoenhanceneuronalgrowthbyoverexpressingcaveolinlevelsin neuronsincombinationwithalreadyexistingpharmacologicalinterventionstotreatindividualsafflictedwith ALS.
