RNA Gain-of-Function in Spinocerebellar Ataxia Type 8 英文参考文献.docVIP

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RNA Gain-of-Function in Spinocerebellar Ataxia Type 8 英文参考文献.doc

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RNA Gain-of-Function in Spinocerebellar Ataxia Type 8 英文参考文献

RNAGain-of-FunctioninSpinocerebellarAtaxiaType8 RandyS.Daughters1,2,DanielL.Tuttle3,4,WangcaiGao5,YoshioIkeda1,2,MelindaL.Moseley1,2 TimothyJ.Ebner5,MauriceS.Swanson3,4,LauraP.W.Ranum1,2 , * 1Department ofGenetics, CellBiology, and Development, University ofMinnesota, Minneapolis,Minnesota, United States ofAmerica, 2Institute ofHuman Genetics, University of Minnesota, Minneapolis, Minnesota, United States of America, 3Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida,UnitedStatesofAmerica,4GeneticsInstitute,UniversityofFlorida,Gainesville,Florida,UnitedStatesofAmerica,5DepartmentofNeuroscience,Universityof Minnesota,Minneapolis,Minnesota,UnitedStatesofAmerica Abstract Microsatellite expansions cause a number of dominantly-inherited neurological diseases. Expansions in coding-regions causeproteingain-of-functioneffects,whilenon-codingexpansionsproducetoxicRNAsthatalterRNAsplicingactivitiesof MBNLandCELFproteins.Bi-directionalexpressionofthespinocerebellarataxiatype8(SCA8)CTGCAGexpansionproduces CUG expansion RNAs(CUGexp) fromthe ATXN8OS gene anda nearly purepolyglutamine expansion protein encodedby ATXN8CAGexp transcriptsexpressedintheoppositedirection.Here,wepresentthreelinesofevidencethatRNAgain-of- function plays asignificant role in SCA8: 1) CUGexp transcripts accumulate as ribonuclear inclusions that co-localize with MBNL1inselectedneuronsinthebrain;2)lossofMbnl1enhancesmotordeficitsinSCA8mice;3)SCA8CUGexptranscripts triggersplicingchangesandincreasedexpressionoftheCUGBP1-MBNL1regulatedCNStarget,GABA-Atransporter4(GAT4/ Gabt4).InvivoopticalimagingstudiesinSCA8miceconfirmthatGabt4upregulationisassociatedwiththepredictedlossof GABAergicinhibitionwithinthegranularcelllayer.ThesedatademonstratethatCUGexptranscriptsdysregulateMBNL/CELF regulatedpathwaysinthebrainandprovidemechanisticinsightintotheCNSeffectsofotherCUGexpdisorders.Moreover, ourdemonstrationthatrelativelyshortCUGexptranscriptscauseRNAgain-of-functioneffects