Pro-Survival Role for Parkinsons Associated Gene DJ-1 Revealed in Trophically Impaired Dopaminergic Neurons 英文参考文献.docVIP

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Pro-Survival Role for Parkinsons Associated Gene DJ-1 Revealed in Trophically Impaired Dopaminergic Neurons 英文参考文献.doc

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Pro-Survival Role for Parkinsons Associated Gene DJ-1 Revealed in Trophically Impaired Dopaminergic Neurons 英文参考文献

Pro-SurvivalRoleforParkinson’sAssociatedGeneDJ-1 RevealedinTrophicallyImpairedDopaminergicNeurons LiviuAron1,PontusKlein1,Thu-TrangPham2,EdgarR.Kramer3,WolfgangWurst2,Ru¨digerKlein1* 1Department of Molecular Neurobiology, Max Planck Institute of Neurobiology, Martinsried, Germany, 2Helmholtz Center Munich, Technical University of Munich, NationalCenterforDementiaResearch,Neuherberg,Germany,3CenterforMolecularNeurobiology,Hamburg,Germany Abstract Themechanismsunderlyingtheselectivedeathofsubstantianigra(SN)neuronsinParkinsondisease(PD)remainelusive. While inactivation of DJ-1, an oxidative stress suppressor, causes PD, animal models lacking DJ-1 show no overt dopaminergic(DA)neurondegenerationintheSN.Here,weshowthatagingmicelackingDJ-1andtheGDNF-receptorRet intheDAsystemdisplayanacceleratedlossofSNcellbodies,butnotaxons,comparedtomicethatonlylackRetsignaling. ThesurvivalrequirementforDJ-1isspecificfortheGIRK2-positivesubpopulationintheSNwhichprojectsexclusivelytothe striatumandismorevulnerableinPD.UsingDrosophilagenetics,weshowthatconstitutivelyactiveRetandassociatedRas/ ERK,butnotPI3K/Akt,signalingcomponentsinteractgeneticallywithDJ-1.Doubleloss-of-functionexperimentsindicate thatDJ-1interactswithERKsignalingtocontroleyeandwingdevelopment.Ourstudyuncoversaconservedinteraction betweenDJ-1andRet-mediatedsignalingandanovelcellsurvivalroleforDJ-1inthemouse.Abetterunderstandingofthe molecular connections between trophic signaling, cellular stress and aging could uncover new targets for drug developmentinPD. Citation:AronL,KleinP,PhamT-T,KramerER,WurstW,etal.(2010)Pro-SurvivalRoleforParkinson’sAssociatedGeneDJ-1RevealedinTrophicallyImpaired DopaminergicNeurons.PLoSBiol8(4):e1000349.doi:10.1371/journal.pbio.1000349 AcademicEditor:AlunDavies,CardiffUniversity,UnitedKingdom ReceivedDecember14,2009;AcceptedFebruary24,2010;PublishedApril6,2010 Copyright: ? 2010 Aron et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License