Huntington's Disease Repeat Instability and Pathogenesis

亨廷顿氏病（HD）是一种致命的神经退行性疾病， CAG重复序列超过约36个单位的阈值。扩增的CAG重复序列被翻译成 多聚谷氨酰胺在亨廷顿蛋白的氨基末端延伸，引发细胞死亡的一个子集， 纹状体和皮层的神经元。扩增的CAG重复序列也表现出显著的不稳定性， 生殖系和体细胞组织中。这项研究的长期目标是阐明 导致HD CAG重复不稳定的途径和由HD CAG重复引发的特定神经退行性变 突变亨廷顿蛋白在准确再现人类HD突变的HD基因敲入小鼠中，Msh2 基因是重复不稳定性和早期纹状体表型的修饰物。在这项研究中，我们将测试 假设Msh2在错配修复途径中起作用以改变CAG重复序列的不稳定性和早期 HD基因敲入小鼠中的表型。我们将用缺乏特异性错配的小鼠进行遗传杂交， 修复基因和Msh2的ATP酶结构域中携带突变的小鼠品系。这些实验将提供 Msh2在突变型HD的CAG重复不稳定性和表型表达中的作用的机制洞察 等位基因确定候选DMA修复基因是否是人类HD发病年龄的调节因子 遗传关联研究将使用发病年龄偏离 通过CAG重复大小预测的值。为了进一步了解Msh2修饰 重复不稳定和早期纹状体疾病的小鼠，我们将产生Msh2的条件性敲除。 使用Cre-loxP系统的基因。我们将使用Camklla- 驱动的Cre转基因来测试Msh2在纹状体神经元中起作用以改变不稳定性和早期 表型总之，这些研究将提供深入了解重复不稳定性的机制， 发病机制，导致合理的治疗策略，旨在减缓或停止这种毁灭性的疾病。

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by the expansion of a polymorphic CAG repeat tract beyond a threshold of ~ 36 units. The expanded CAG repeat is translated into a polyglutamine stretch at the amino-terminus of the huntingtin protein, triggering cell death in a subset of neurons in the striatum and cortex. The expanded CAG repeat also exhibits dramatic instability in the germline and in somatic tissues. The long-term goals of this research are to elucidate the molecular pathways that underlie the instability of the HD CAG repeat and the specific neurodegeneration triggered by mutant huntingtin. In HD knock-in mice, which accurately recapitulate the human HD mutation, the Msh2 gene is a modifier of repeat instability and an early striatal phenotype. In this study we will test the hypothesis that Msh2 acts in the mismatch repair pathway to modify CAG repeat instability and early phenotypes in HD knock-in mice. We will perform genetic crosses with mice deficient in specific mismatch repair genes and mouse line carrying a mutation in Msh2's ATPase domain. These experiments will provide mechanistic insight into Msh2's role in CAG repeat instability and phenotypic expression of the mutant HD allele. To determine whether candidate DMA repair genes are modifiers of the age of onset of HD in humans genetic association studies will be performed using 'extreme' individuals with onset ages deviating from values predicted by CAG repeat size. To gain further insight into the mechanism by which Msh2 modifies repeat instability and early striatal disease in the mouse we will generate a conditional knockout of the Msh2 gene using the Cre-loxP system. We will specifically inactivate Msh2 in forebrain neurons using a Camklla- driven Cre transgene to test the hypothesis that Msh2 acts in striatal neurons to modify instability and early phenotypes. Together, these studies will provide insight into mechanisms of repeat instability and pathogenesis, leading to rational therapeutic strategies aimed at slowing or halting this devastating disease.