A role of astrocytes in mediating postnatal neurodegeneration in Glutaric acidemia‐type 1

摘要

Astrocytesarecrucialforpostnataldevelopmentofneuronalnetworks,axonmyelinationandneurovascularstructures.Defectsinastrocytegenerationormaturationareassociatedwithsevereneurologicaldevelopmentaldisorders.GlutaricacidemiatypeI(GAI),aninheritedneurometabolicdisordercharacterizedbyaccumulationofglutaric(GA)and3‐hydroxyglutaricacids,showsaparadigmaticpostnatalneuropathologycharacterizedbymassivedegenerationofneuronsinthestriatum.Whilethedisorderiscausedbygeneticmutationsonglutaryl‐CoAdehydrogenase,theneurologicaldefectsusuallystartmonthsafterbirth.PathogenesisofGAIhasremainedlargelyunknown,andspecifically,itisunclearhowaccumulationofGAImetabolitesmayresultinneurodegeneration.RecentevidencesupportsaGAImodelinvolvingprimarydefectiveastrocytematurationleadingtoaco‐morbidspectrumofneurologicsymptomssimilartothoseofpatients.AstrocytesarevulnerabletoGAImetabolites,butinsteadofdying,theyfollowlong‐lastingphenotypicchangesleadingtostriatalneurondegenerationaswellasdefectivemyelinationandbloodbrainbarriermaturation.Here,wesummarizedrecentfindingsonthepathogenicroleofGA‐damagedastrocytesinGAIanddiscussifastrocytedysfunctionmaybeatargetoftherapeuticinterventions...