ATXN2-CAG42 Sequesters PABPC1 into Insolubility and Induces FBXW8 in Cerebellum of Old Ataxic Knock-In Mice 英文参考文献.docVIP

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ATXN2-CAG42 Sequesters PABPC1 into Insolubility and Induces FBXW8 in Cerebellum of Old Ataxic Knock-In Mice 英文参考文献.doc

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ATXN2-CAG42 Sequesters PABPC1 into Insolubility and Induces FBXW8 in Cerebellum of Old Ataxic Knock-In Mice 英文参考文献

ATXN2-CAG42SequestersPABPC1intoInsolubilityand InducesFBXW8inCerebellumofOldAtaxicKnock-In Mice EwaDamrath1,MelanieV.Heck1,SuzanaGispert1,MekhmanAzizov1,JoachimNowock1, CarolaSeifried1,UdoRu¨b2,MichaelWalter3,GeorgAuburger1* 1Experimental Neurology, Department of Neurology, Goethe University Medical School, Frankfurt am Main, Germany, 2Department of Clinical Neuroanatomy, Dr. Senckenbergisches Chronomedizinisches Institut, Goethe University Medical School, Frankfurt am Main, Germany, 3Institute of Medical Genetics, Eberhard Karls University,Tu¨bingen,Germany Abstract Spinocerebellar Ataxia Type 2 (SCA2) is caused by expansion of a polyglutamine encoding triplet repeat in the human ATXN2genebeyond(CAG)31.Thisisthoughttomediatetoxicgain-of-functionbyproteinaggregationandtoaffectRNA processing,resultingindegenerativeprocessesaffectingpreferentiallycerebellarneurons.Asafaithfulanimalmodel,we generated a knock-in mouse replacing the single CAG of murine Atxn2 with CAG42, a frequent patient genotype. This expansion sizewas inherited stably. Themice showedphenotypes withreduced weightandlater motorincoordination. Although brain Atxn2 mRNA became elevated, soluble ATXN2 protein levels diminished over time, which might explain partial loss-of-function effects. Deficits in soluble ATXN2 protein correlated with the appearance of insoluble ATXN2, a progressivefeatureincerebellumpossiblyreflectingtoxicgains-of-function.SinceinvitroATXN2overexpressionwasknown toreducelevelsofitsproteininteractorPABPC1,westudiedexpansioneffectsonPABPC1.Incortex,PABPC1transcriptand soluble and insoluble protein levels were increased. In the more vulnerable cerebellum, the progressive insolubility of PABPC1wasaccompaniedbydecreasedsolubleproteinlevels,withPABPC1mRNAshowingnocompensatoryincrease.The sequestration of PABPC1 into insolubility by ATXN2 function gains was validated in human cell culture. To understand consequencesonmRNAprocessing,transcriptomeprofilesatmediumandoldageinthreedifferentti