AutophagyinNeuronsAndreaK.H.Stavoe1,ErikaL.F.Holzbaur21DepartmentofPhysiology,UniversityofPennsylvaniaPerelmanSchoolofMedicine;2DepartmentofPhysiology,UniversityofPennsylvaniaPerelmanSchoolofMedicine;AbstractAutophagyisthemajorcellularpathwaytodegradedysfunctionalorganellesandproteinaggregates.Autophagyisparticularlyimportantinneurons,terminallydifferentiatedcellsthatmustlastthelifetimeoftheorganism.Therearebothconstitutiveandstress-inducedpathwaysforautophagyinneurons,whichcatalyzetheturnoverofagedordamagedmitochondria,endoplasmicreticulum,othercellularorganelles,andaggregatedproteins.Thesepathwaysarerequiredinneurodevelopmentaswellasinthemaintenanceofneuronalhomeostasis.Herewereviewthecorecomponentsofthepathwayforautophagosomebiogenesis,aswellasthecellbiologyofbulkandselectiveautophagyinneurons.Finally,wediscusstheroleofautophagyinneuronaldevelopment,homeostasis,andaging,andthelinksbetweendeficitsinautophagyandneurodegeneration.KeywordsAutophagy;mitophagy;ERphagy;aggrephagy;neuronalhomeostasis;neurodegenerationINTRODUCTION:DEGRADATIVEPATHWAYSINTHENEURONNeuronsarepost-mitoticandlong-livedcells.Bothneurodevelopmentandthelong-termmaintenanceofneuronalhealthrequireeffectiveremovalofaggregatedproteinsandagedordefectiveorganelles.Geneticandcellularstudiesindicatethatdefectsinproteinandorganelleturnovercloselycorrelatewithcellularstress,degeneration,anddeath.Multipledegradativepathwaysareatworkinneurons,suchasthedegradationofmisfoldedproteinsviatheubiquitin-proteasomepathway(Bingol&Sheng2011).Proteindegradationalsooccursviatheendolysosomaltraffickingpathway(Lie&Nixon2018,Winckleretal.2018),aswellasbychaperone-mediatedautophagyandendosomalmicroautophagy(Tekirdag&Cuervo2018).Recentlyidentifiedpathwaysmayalsocontributetotheclearanceofmisfoldedoraggregatedproteinsinneurons,suchastheMAGIC(mitochondriaasguardianincytosol)pathwayinvolvingimportofmisfoldedproteinsintomitochondria(Ruanetal.2017).Correspondingauthor:ErikaL.F.Holzbaur,DepartmentofPhysiology,PerelmanSchoolofMedic...
