A Mouse Model of RNA-induced Neurotoxcity

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Toxicity of RNA transcripts containing long CUG repeats, a novel mechanism of disease pathogenesis, was recently described in myotonic dystrophy type 1 (DM1), the most common form of adult onset muscular dystrophy. The precise mechanism by which CUG expansions lead to cell toxicity is unclear, though misregulation of splicing may be involved. Our group recently identified an autosomal dominant disorder, Huntington's disease-like 2 (HDL2), with clinical and pathological features almost identical to Huntington's disease (HD), a relentlessly progressive adult onset neurodegenerative disorder. Like HD, HDL2 is caused by a CAG/CTG expansion mutation. To our surprise, the pathogenesis of HDL2, like DM1 and unlike HD, appears to arise at least in part from the toxic effect of RNA transcripts containing long CUG repeats. To test the hypothesis that untranslated CUG expansions can lead to neurotoxicity in the mammalian brain, we propose to generate a transgenic mouse specifically expressing an expanded CUG repeat in the brain. In Specific Aim 1, we will generate CUG transgenic mice, using an untranslatable construct that contains a short fragment of JPH3 with either a normal or an expanded CTG repeat under the control of the brain-specific PrP promoter. In Specific Aim 2, the behavioral, motoric, and pathological phenotype of these mice will be examined. In Specific Aim 3, specific characteristics of CUG repeat expansion diseases will be examined in the mice, with an emphasis on RNA foci and protein aggregation. We predict that the expanded CUG repeat will lead to neurotoxicity, evident in motor behavior and neuropathology. If this prediction is correct, the mice generated here will become invaluable tools for dissecting the pathogenic pathways of DM1, HD, and HDL2. Finding the points of pathogenic convergence in these diseases may provide novel leads for the development of rational therapeutics.