rna gain-of-function in spinocerebellar ataxia type 8rna在脊髓小脑的功能共济失调型8.pdfVIP

RNA Gain-of-Function in Spinocerebellar Ataxia Type 8 1,2 3,4 5 1,2 1,2 Randy S. Daughters , Daniel L. Tuttle , Wangcai Gao , Yoshio Ikeda , Melinda L. Moseley , Timothy J. Ebner5, Maurice S. Swanson3,4, Laura P. W. Ranum1,2* 1 Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, United States of America, 2 Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota, United States of America, 3 Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States of America, 4 Genetics Institute, University of Florida, Gainesville, Florida, United States of America, 5 Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota, United States of America Abstract Microsatellite expansions cause a number of dominantly-inherited neurological diseases. Expansions in coding-regions cause protein gain-of-function effects, while non-coding expansions produce toxic RNAs that alter RNA splicing activities of MBNL and CELF proteins. Bi-directional expression of the spinocerebellar ataxia type 8 (SCA8) CTG CAG expansion produces CUG expansion RNAs (CUGexp) from the ATXN8OS gene and a nearly pure polyglutamine expansion protein encoded by ATXN8 CAGexp transcripts expressed in the opposite direction. Here, we present three lines of evidence that RNA gain-of- function plays a significant role in SCA8: 1) CUGexp transcripts accumulate as ribonuclear inclusions that co-localize with MBNL1 in selected neurons in the brain; 2) loss of Mbnl1 enhances motor deficits in SCA8 mice; 3) SCA8 CUGexp transcripts trigger splicing changes and increased expression of the CUGBP1-MBNL