CDK5 Is Essential for Soluble Amyloid β-Induced Degradation of GKAP and Remodeling of the Synaptic Actin Cytoskeleton 英文参考文献.docVIP

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CDK5 Is Essential for Soluble Amyloid β-Induced Degradation of GKAP and Remodeling of the Synaptic Actin Cytoskeleton 英文参考文献.doc

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CDK5 Is Essential for Soluble Amyloid β-Induced Degradation of GKAP and Remodeling of the Synaptic Actin Cytoskeleton 英文参考文献

CDK5IsEssentialforSolubleAmyloidb-Induced DegradationofGKAPandRemodelingoftheSynaptic ActinCytoskeleton FrancescoRoselli1,2*¤,PaoloLivrea2,OsborneF.X.Almeida1* 1NeuroadaptationGroup,MaxPlanckInstituteofPsychiatry,Munich,Germany,2DepartmentofNeurologicalandPsychiatricSciences,UniversityofBari,Bari,Italy Abstract The early stages of Alzheimer’s disease are marked by synaptic dysfunction and loss. This process results from the disassemblyanddegradationofsynapticcomponents,inparticularofscaffoldingproteinsthatcomposethepost-synaptic density (PSD), namely PSD95, Homer and Shank. Here we investigated in rat frontal cortex dissociated culture the mechanismsinvolvedinthedownregulationofGKAP(SAPAP1),whichlinksthePSD95complextotheShankcomplexand cytoskeletalstructureswithinthePSD.WeshowthatAbcausestherapidlossofGKAPfromsynapsesthroughapathway thatcriticallyrequirescdk5activity,andissetinmotionbyNMDARactivityandCa2+influx.WeshowthatGKAPisadirect substrate of cdk5 and that its phosphorylation results in polyubiquitination and proteasomal degradation of GKAP and remodeling(collapse)ofthesynapticactincytoskeleton;thelattereffectisabolishedinneuronsexpressingGKAPmutants thatareresistanttophosphorylationbycdk5.Giventhatcdk5alsoregulatesdegradationofPSD95,theseresultsunderscore thecentralpositionofcdk5inmediatingAb-inducedPSDdisassemblyandsynapseloss. Citation:RoselliF,LivreaP,AlmeidaOFX(2011)CDK5IsEssentialforSolubleAmyloidb-InducedDegradationofGKAPandRemodelingoftheSynapticActin Cytoskeleton.PLoSONE6(7):e23097.doi:10.1371/journal.pone.0023097 Editor:SergioT.Ferreira,FederalUniversityofRiodeJaneiro,Brazil ReceivedMarch9,2011;AcceptedJuly11,2011;PublishedJuly29,2011 Copyright: ? 2011 Roselli et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited. Funding: FRwas supported byaMaxPlanck Institute ofPsychiatryfello