Allele-Specific RNA Silencing of Mutant Ataxin-3 Mediates Neuroprotection in a Rat Model of Machado-Joseph Disease 英文参考文献.docVIP

Allele-SpecificRNASilencingofMutantAtaxin-3 MediatesNeuroprotectioninaRatModelofMachado- JosephDisease SandroAlves1,2,4,IsabelNascimento-Ferreira1,2,Gwennae¨lleAuregan4,5,RaymondeHassig4,5,Noe¨lle Dufour4,5,EmmanuelBrouillet4,5,MariaC.PedrosodeLima1,3,PhilippeHantraye4,5,Lu?′sPereirade Almeida1,2.*,NicoleDe′glon4,5. 1Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal, 2Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal, 3Faculty of Sciences,UniversityofCoimbra,Coimbra,Portugal,4CEA,InstituteofMolecularImaging(I2BM)andMolecularImagingResearchCenter(MIRCen),Orsay,France,5CNRS URA2210,Orsay,France Abstract RecentstudieshavedemonstratedthatRNAiisapromisingapproachfortreatingautosomaldominantdisorders.However, discrimination between wild-type and mutant transcripts is essential, to preserve wild-type expression and function. A single nucleotidepolymorphism (SNP)is present in morethan70% of patients withMachado-Joseph disease (MJD).We investigated whether this SNP could be used to inactivate mutant ataxin-3 selectively. Lentiviral-mediated silencing of mutanthumanataxin-3wasdemonstratedinvitroandinaratmodelofMJDinvivo.Theallele-specificsilencingofataxin-3 significantlydecreasedtheseverityoftheneuropathologicalabnormalitiesassociatedwithMJD.Thesedatademonstrate thatRNAihaspotentialforuseinMJDtreatmentandconstitutethefirstproof-of-principleforallele-specificsilencinginthe centralnervoussystem. Citation:AlvesS,Nascimento-FerreiraI,AureganG,HassigR,DufourN,etal.(2008)Allele-SpecificRNASilencingofMutantAtaxin-3MediatesNeuroprotectionin aRatModelofMachado-JosephDisease.PLoSONE3(10):e3341.doi:10.1371/journal.pone.0003341 Editor:MarkR.Cookson,NationalInstitutesofHealth,UnitedStatesofAmerica ReceivedJuly7,2008;AcceptedSeptember11,2008;PublishedOctober8,2008 Copyright: ? 2008 Alves et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricteduse,distribution,and