A Mouse Model of RNA-induced Neurotoxcity

含有长CUG重复序列的RNA转录物的毒性，一种新的疾病发病机制， 最近在强直性肌营养不良1型（DM 1）中被描述，DM 1是成人发病的最常见形式 肌肉萎缩症CUG扩增导致细胞毒性的确切机制尚不清楚， 尽管可能涉及剪接的错误调节。我们小组最近发现了一种常染色体显性遗传 亨廷顿舞蹈病样2（HDL 2），临床和病理特征几乎相同， 亨廷顿病（HD）是一种持续进展的成人发病的神经退行性疾病。像高清一样， HDL 2是由CAG/CTG扩增突变引起的。令我们惊讶的是，HDL 2的发病机制，如 与HD不同，DM 1似乎至少部分地由RNA转录物的毒性作用引起，所述RNA转录物含有 长CUG重复。为了检验未翻译的CUG扩增可导致神经毒性的假设， 哺乳动物的大脑，我们建议产生一个转基因小鼠特异性表达扩大的 在大脑中重复。在具体目标1中，我们将使用 一种不可翻译的构建体，包含具有正常或扩增CTG的JPH 3短片段 在脑特异性PrP启动子的控制下重复。在具体目标2中，行为、运动和 将检查这些小鼠的病理表型。在具体目标3中，CUG的具体特征 将在小鼠中检查重复扩增疾病，重点是RNA灶和蛋白质 聚合来我们预测扩展的CUG重复序列将导致神经毒性，在运动神经中明显。 行为和神经病理学。如果这个预测是正确的，这里产生的老鼠将变得无价 用于剖析DM 1、HD和HDL 2的致病途径的工具。寻找致病点 这些疾病的融合可能为合理治疗的发展提供新的线索。

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.