Huntington's Disease Repeat Instability and Pathogenesis

摘要 亨廷顿病(HD)是一种毁灭性和致命性的神经退行性疾病，由 HTT基因中CAG重复序列的多态可导致细胞死亡，并具有神经元特异性 纹状体和皮质。尽管潜在的基因突变是在25年前发现的，但仍然有 尽管作出了广泛的努力，但没有治愈或有效的治疗。HTT CAG重复突变高度不稳定 在传递给后代和肉体上。值得注意的是，重复经历了戏剧性的组织- 特定的躯体扩张，特别是在疾病中受影响的大脑区域，强烈表明 靶组织中体细胞HTT CAG长度的增加参与了HD的发病。最新人类基因 数据提供了令人信服的支持，支持躯体CAG的扩张是HD致病几率的驱动因素， 确定DNA修复基因是HD患者疾病发病的修饰基因，其中许多基因修改了体细胞CAG 精确的遗传HD敲入小鼠模型的扩展。在这项研究中，我们将进行实验，以深入 在许多基本层面上询问这些修饰基因。在目标1中，我们将使用基因实验 在小鼠身上测试改变躯体扩张对疾病表达的影响。在《目标2》中，我们将表演 在患者细胞和小鼠模型中进行生化研究，以了解其作用机制和 功能后果是人类修饰语的变体。在目标3中，我们将检查人类修改者的影响 脑内特定细胞类型CAG不稳定性和基因表达的变异。加在一起，这些 由人类基因数据驱动的实验将提供对疾病机制的关键洞察 改进HD，并将指导针对CAG扩展的治疗方法的发展。

ABSTRACT Huntington’s disease (HD) is a devastating and fatal neurodegenerative disorder caused by the expansion of a polymorphic CAG repeat in the HTT gene that triggers cell death with specificity towards neurons in the striatum and cortex. Although the underlying genetic mutation was discovered over 25 years ago, there is still no cure or effective treatment despite extensive efforts. The HTT CAG repeat mutation is highly unstable both in transmissions to subsequent generations and somatically. Notably the repeat undergoes dramatic tissue- specific somatic expansion, particularly in the brain regions affected in the disorder, strongly suggesting that somatic HTT CAG length increases in target tissues contribute to HD pathogenesis. Recent human genetic data provide compelling support for somatic CAG expansion as a driver of the rate of HD pathogenesis, identifying DNA repair genes as modifiers of disease onset in HD patients, many of which modify somatic CAG expansion in accurate genetic HD knock-in mouse models. In this study, we will perform experiments to deeply interrogate these modifier genes at a number of fundamental levels. In Aim 1 we will use genetic experiments in the mouse to test the impact of altering somatic expansion on disease expression. In Aim 2, we will perform biochemical studies in patient cells and in mouse models to understand the mechanism of action and functional consequences a human modifier variant. In Aim 3 we will examine the impacts of human modifier variation on CAG instability and gene expression in specific cell types in the brain. Together, these experiments that are driven by human genetic data, will provide critical insight into mechanisms of disease modification in HD and will guide development of therapeutics targeting CAG expansion.