Nature Genetics 38, 758 - 769 (2006)
Published online: 25 June 2006; | doi:10.1038/ng1827
Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8Melinda L Moseley1, 2, Tao Zu1, 2, Yoshio Ikeda1, 2, Wangcai Gao4, Anne K Mosemiller1, 2, Randy S Daughters1, 2, Gang Chen4, Marcy R Weatherspoon1, 2, H Brent Clark3, 5, Timothy J Ebner4, John W Day2, 5 & Laura P W Ranum1, 21
Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota
55455, USA. 2
Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota
55455, USA. 3
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota
55455, USA. 4
Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota
55455, USA. 5
Department of Neurology, University of Minnesota, Minneapolis, Minnesota
55455, USA.
Correspondence should be addressed to Laura P W Ranum ranum001@umn.edu We previously reported that a (CTG)n expansion causes spinocerebellar ataxia type 8 (SCA8), a slowly progressive ataxia with reduced penetrance. We now report a transgenic mouse model in which the full-length human SCA8 mutation is transcribed using its endogenous promoter. (CTG)116 expansion, but not (CTG)11 control lines, develop a progressive neurological phenotype with in vivo imaging showing reduced cerebellar-cortical inhibition. 1C2-positive intranuclear inclusions in cerebellar Purkinje and brainstem neurons in SCA8 expansion mice and human SCA8 autopsy tissue result from translation of a polyglutamine protein, encoded on a previously unidentified antiparallel transcript (ataxin 8, ATXN8) spanning the repeat in the CAG direction. The neurological phenotype in SCA8 BAC expansion but not BAC control lines demonstrates the pathogenicity of the (CTG-CAG)n expansion. Moreover, the expression of noncoding (CUG)n expansion transcripts (ataxin 8 opposite strand, ATXN8OS) and the discovery of intranuclear polyglutamine inclusions suggests SCA8 pathogenesis involves toxic gain-of-function mechanisms at both the protein and RNA levels.
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