Spinalmuscularatrophy(SMA)isaneurodegenerativediseasecharacterizedbymotorneuronlossandskeletal muscleatrophy.SMAiscausedbyubiquitousdeficiencyintheSMNproteinandistheleadinggeneticcauseof infantmortality.Todate,mostSMAtherapeuticapproacheshavefocusedonincreasingSMNexpressionand SMN-inducingtherapieshaverecentlybeenapprovedforSMA.However,thesetherapiesalonedonotprovide acure orSMA ndnotallpatientsrespond totreatment.Therefore,it remains essentialtounderstand the underlyingmechanismsofSMAand identifySMN-independent therapeuticapproaches thatcanenhancethe benefitofSMN-inducingstrategiesthroughcombinatorial treatment.Inthis context,motorneurondeath isan irreversible pathogenichallmarkofSMA.Therefore,preventingmotorneurondegeneration has fundamental clinicalimplicationsforSMAtherapyandcouldextendthewindowofopportunityforSMN-inducingtherapiesto exert their effect.However,thisishinderedby limited knowledge ofthedeath pathway and availabilityof druggable-targetsforhaltingthisprocess.Thisprojectaimstoaddresstheseoutstandingissuesbyinvestigating themechanismsunderlyingtheinitiationandexecutionofmotorneurondegenerationinSMAaswellasvalidate thetherapeuticpotentialof pharmacologicallytargetingthispathway in mousemodels of the disease.The premiseofourproposedworkisthattheneurodegenerativepathwayofSMAmotorneuronsrepresentsatarget- richdomainforthediscoveryofdisease-modifyingpharmacologicalapproachesthatareSMN-independentand suitedforcombinatorialtreatmentofSMA.Buildingonourpublishedandpreliminarystudies,wewillcharacterize theupstream mechanismsdrivingmotorneuron death inSMAbased onourhypothesis thatSMN deficiency triggersap38MAPK/p53-dependentneurodegenerativepathway (Aim1).To broaden the range of candidate targetsfordevelopingSMN-independentneuroprotectiveapproachesforSMA,wewilldeterminetheexecution mechanismsofmotorneurondeaththroughtheidentificationandfunctionalcharacterizationofthedownstream effectorsofp53-dependent neurodegenerationinSMA(Aim2).Lastly, we willleverageon theavailabilityof a highlyselective,brainpermeableinhibitortotestthehypothesisthatp38MAPKactivationisasharedpathogenic mechanism associated with motor neuron death across mouse modelsofSMAwithvaryingdiseaseseverity whose inhibition is a viable therapeutic approach (Aim 3).Wewillalsoevaluatewhether pharmacological inhibitionofp38MAPKenablesenhancedsynapticrewiringbypreservingSMAmotorneuronsinaparadigmof combinatorialtreatmentwithSMNupregulation.Successfulaccomplishmentofourobjectiveshasthepotential toprovidekey insights intothe mechanismsofmotorneurondeath inSMA, identifynewdiseasemarkersand candidate targets tohalttheneurodegenerativeprocess,andestablishpharmacologicalapproachesfor neuroprotectiontobeusedincombinatorialtreatmentofthediseasewithSMN-inducingtherapies.
Breakthrough SMN-inducing therapies have recently been approved by FDA for the treatment of SMA. However, they do not provide a cure and therapeutic approaches that address unmet needs of SMA patients by enhancing the clinical benefit of SMN-inducing therapies through combinatorial treatment are highly sought after. To address this issue, our project aims to elucidate the mechanisms underlying the initiation and execution of motor neuron degeneration in SMA as well as establish the therapeutic potential of SMN-independent, pharmacological targeting of this pathway for neuroprotection.
