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Microsatellite expansions cause a number of dominantlyinherited neurological diseases including myotonic dystrophy (DM1 and DM2), Huntington’s disease (HD and HDL2) and several forms of spinocerebellar ataxia (SCA) . Expansions located in coding-regions cause dominant protein gainof-function effects and non-coding expansions (DM and DM2) produce toxic RNA gain-of-function effects that in muscle have been shown to alter RNA splicing activities of MBNL and CELF proteins. We previously reported that a (CTG)n expansion causes spinocerebellar ataxia type 8 (SCA8). Because the SCA 8 expansion is transcribed, alternatively spliced, and polyadenylated in the CTG orientation we initially proposed that SCA8 is caused by an RNA gain-offunction mechanism similar to myotonic dystrophy. To elucidate the molecular events that cause SCA8, we developed a BAC transgenic mouse model in which the full length human SCA8 gene is expressed using its endogenous promoter. (CTG)116 expansion, but not (CTG)11 control lines, develop a progressive neurological phenotype and a loss of cerebellar cortical inhibition. Surprisingly, we found 1C2-intranuclear inclusions in Purkinje cells in SCA8 expansion mice and human SCA8 autopsy tissue result from translation of a nearly pure polyglutamine protein encoded on a previously unidentified anti-parallel transcript spanning the repeat in the CAG direction. The neurological phenotype found in the SCA8 BAC expansion lines but not BAC control lines demonstrates the pathogenicity of the (CTG・CAG)n expansion. We discussed three lines of evidence that SCA8 CUG transcripts cause RNA gain of function effects in the CNS. First, we demonstrate SCA8 CUG transcripts form ribonuclear inclusions that co-localize with MBNL1. Second, we show that genetic loss ofMbnl1 enhances motor coordination deficits in SCA8 mice. Third we show the GABA-A transporter-4 (Gabt4) gene, which is dramatically upregulated in SCA8, is a misregulated MBNL CELF splicing target. These data demonstrate for the first time that CUG transcripts dysregulate MBNL CELF regulated pathways in the brain and provide mechanistic insight into the CNS effects of other CUG disorders (DM, HDL2) . While functional evidence for RNA gain-of-function effects is presented here, the additional discovery of intranuclear polyglutamine inclusions in SCA8 suggests disease pathogenesis is mediated by toxic gain-of-function mechanisms at both the protein and RNA levels. Additionally, the growing number of bidirectionallyexpressed genes in the genome suggests unrecognized CUG RNAs contribute to some of the polyglutamine CAG・CTG disorders Please see Daughters et al. , Plos Genetics. Funding from the NIH (PO1NS058901, NS40389, AR46799), the Muscular Dystrophy Association and the National Ataxia Foundation is gratefully acknowledged.

Double the Trouble: Bidirectional Expression of the SCA8 CAG/CTG Expansion Mutation -Evidence for RNA and Protein Gain of Function Effects