Neuropathology in Mice Expressing Mouse Alpha-Synuclein 英文参考文献.docVIP

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Neuropathology in Mice Expressing Mouse Alpha-Synuclein 英文参考文献.doc

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Neuropathology in Mice Expressing Mouse Alpha-Synuclein 英文参考文献

NeuropathologyinMiceExpressingMouseAlpha- Synuclein ClausRieker1,KumleshK.Dev2,KatjaLehnhoff1,SamuelBarbieri1,IwonaKsiazek3¤,SabineKauffmann1, SimoneDanner1,HeinrichSchell4,CindyBoden4,MarkusA.Ruegg3,PhilippJ.Kahle4,Hermanvander Putten1,DeryaR.Shimshek1* 1Novartis Institutes forBioMedical Research, Novartis Pharma AG,Basel,Switzerland, 2Department ofPhysiology,School ofMedicine, TrinityCollege Dublin, Dublin, Ireland,3NeurobiologyBiozentrum,UniversityofBasel,Basel,Switzerland,4DepartmentofNeurodegeneration,HertieInstituteforClinicalBrainResearchandGerman CenterforNeurodegenerativeDiseases,UniversityofTu¨bingen,Tu¨bingen,Germany Abstract a-Synuclein (aSN) in human is tightly linked both neuropathologically and genetically to Parkinson’s disease (PD) and relateddisorders.Disease-causingpropertiesinvivoofthewildtypemouseortholog(maSN),whichcarriesathreonineat position 53 like the A53T human mutant version that is genetically linked to PD, were never reported. To this end we generatedmouselinesthatexpressmaSNincentral neuronsatlevelsreachinguptosix-fold comparedtoendogenous maSN.UnliketransgenicmiceexpressinghumanwildtypeormutantformsofaSN,thesemaSNtransgenicmiceshowed pronounced ubiquitin immunopathology in spinal cord and brainstem. Isoelectric separation of maSN species revealed multiple isoforms including two Ser129-phosphorylated species in the most severely affected brain regions. Neuronal Ser129-phosphorylatedaSNoccuredingranularandsmallfibrillaraggregatesandpathologicalstainingpatternsinneurites occasionally revealed a striking ladder of small alternating segments staining either for Ser129-phosphorylated aSN or ubiquitin but not both. Axonal degeneration in long white matter tracts of the spinal cord, with breakdown of myelin sheathsanddegenerationofneuromuscularjunctionswithlossofintegrityofthepresynapticneurofilamentnetworkin maSNtransgenicmice,wassimilartowhatwehavereportedformiceexpressinghumanaSNwildtypeormutantforms.In hippocampal neurons, themaS