Endogenous Nmnat2 Is an Essential Survival Factor for Maintenance of Healthy Axons 英文参考文献.docVIP

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Endogenous Nmnat2 Is an Essential Survival Factor for Maintenance of Healthy Axons 英文参考文献.doc

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Endogenous Nmnat2 Is an Essential Survival Factor for Maintenance of Healthy Axons 英文参考文献

EndogenousNmnat2IsanEssentialSurvivalFactorfor MaintenanceofHealthyAxons JonathanGilley,MichaelP.Coleman* TheBabrahamInstitute,BabrahamResearchCampus,Cambridge,UnitedKingdom Abstract Themoleculartriggersforaxondegenerationremainunknown.WeidentifyendogenousNmnat2asalabileaxonsurvival factor whose constant replenishment by anterograde axonal transport is a limiting factor for axon survival. Specific depletionofNmnat2issufficienttoinduceWallerian-likedegenerationofuninjuredaxonswhichendogenousNmnat1and Nmnat3cannotprevent.Nmnat2isbyfarthemostlabileNmnatisoformandisdepletedindistalstumpsofinjuredneurites beforeWalleriandegenerationbegins.Nmnat2turnoverisequallyrapidininjuredWldSneurites,despitedelayedneurite degeneration,showingitisnotaconsequenceofdegenerationandalsothatWldSdoesnotstabilizeNmnat2.Depletionof Nmnat2belowathresholdlevelisnecessaryforaxondegenerationsinceexogenousNmnat2canprotectinjuredneurites when expressed at high enough levels to overcome its short half-life. Furthermore, proteasome inhibition slows both Nmnat2turnoverandneuritedegeneration.WeconcludethatendogenousNmnat2preventsspontaneousdegenerationof healthy axons and propose that, when present, the more long-lived, functionally related WldS protein substitutes for Nmnat2lossafteraxoninjury.EndogenousNmnat2representsanexcitingnewtherapeutictargetforaxonaldisorders. Citation: Gilley J, Coleman MP (2010) Endogenous Nmnat2 Is an Essential Survival Factor for Maintenance of Healthy Axons. PLoS Biol 8(1): e1000300. doi:10.1371/journal.pbio.1000300 AcademicEditor:BenA.Barres,StanfordUniversitySchoolofMedicine ReceivedJuly6,2009;AcceptedDecember18,2009;PublishedJanuary26,2010 Copyright: ?2010 Gilley, Coleman. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited. Funding:ThisworkisfundedbytheUnitedKingdomMedicalResearchCouncil(MRC)Programmegr