Prion Protein Paralog Doppel Protein Interacts with Alpha-2-Macroglobulin A Plausible Mechanism for Doppel-Mediated Neurodegeneration 英文参考文献.docVIP

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Prion Protein Paralog Doppel Protein Interacts with Alpha-2-Macroglobulin A Plausible Mechanism for Doppel-Mediated Neurodegeneration 英文参考文献.doc

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Prion Protein Paralog Doppel Protein Interacts with Alpha-2-Macroglobulin A Plausible Mechanism for Doppel-Mediated Neurodegeneration 英文参考文献

PrionProteinParalogDoppelProteinInteractswith Alpha-2-Macroglobulin:APlausibleMechanismfor Doppel-MediatedNeurodegeneration StefanoBenvegnu`1,DiegoFranciotta2,JoshSussman3¤,AngelaBachi5,ElisabettaZardini2 ,Paola Torreri7,CedricGovaerts3,6,SalvatorePizzo8,GiuseppeLegname1,3,4* 1ScuolaInternazionaleSuperiorediStudiAvanzati-InternationalSchoolforAdvancedStudies(SISSA-ISAS),Trieste,Italy,2IRCCS,Foundation,NeurologicalInstituteC. Mondino,UniversityofPavia,Pavia,Italy,3InstituteforNeurodegenerativeDiseases,4DepartmentofNeurology,UniversityofCaliforniaSanFrancisco,SanFrancisco, California,United StatesofAmerica, 5DIBIT, SanRaffaeleScientificInstitute, Milan, Italy, 6Universite′ Libre deBruxelles,Bruxelles,Belgium, 7NationalCentreforRare Diseases,IstitutoSuperiorediSanita`, Roma,Italy,8DepartmentofPathology,DukeUniversityMedicalCenter,Durham,NorthCarolina,UnitedStatesofAmerica Abstract Doppelprotein(Dpl)isaparalogofthecellularformoftheprionprotein(PrPC),togethersharingcommonstructuraland biochemical properties. Unlike PrPC, which is abundantly expressed throughout the central nervous system (CNS), Dpl proteinexpressionisnotdetectableintheCNS.Interestingly,itsectopicexpressioninthebrainelicitsneurodegenerationin transgenicmice.Here,bycombiningnativeisoelectricfocusingplusnon-denaturingpolyacrylamidegelelectrophoresisand mass spectrometry analysis, we identified two Dpl binding partners: rat alpha-1-inhibitor-3 (a1I3) and, by sequence homology, alpha-2-macroglobulin (a2M), two known plasma metalloproteinase inhibitors. Biochemical investigations C excluded the direct interaction of PrP with either a1I3 or a2M. Nevertheless, enzyme-linked immunosorbent assays and C surfaceplasmonresonanceexperimentsrevealedahighaffinitybindingoccurringbetweenPrP andDpl.Inlightofthese findings, we suggest a mechanism for Dpl-induced neurodegeneration in mice expressing Dpl ectopically in the brain, linkedtoawithdrawalofnaturalinhibitorsofmetalloproteinasesuchasa2M.Interestingly,a2Mhas