Huntington's Disease Repeat Instability and Pathogenesis

摘要 亨廷顿氏病（HD）是一种毁灭性的和致命的神经退行性疾病，其由一种神经系统疾病的扩张引起。 HTT基因中的多态性CAG重复序列，其触发细胞死亡，对神经元具有特异性， 纹状体和皮质。虽然潜在的基因突变在25年前就被发现了，但仍然存在 尽管做了大量努力，但仍无法治愈或有效治疗。HTT CAG重复突变非常不稳定， 在传递给后代和体细胞方面。值得注意的是，重复经历了戏剧性的组织- 特定的躯体扩张，特别是在受疾病影响的大脑区域，强烈表明， 靶组织中的体细胞HTT CAG长度增加有助于HD发病机制。人类遗传学 数据为体细胞CAG扩增作为HD发病率的驱动因素提供了有力的支持， 鉴定DNA修复基因作为HD患者疾病发作的修饰因子，其中许多修饰体细胞CAG 在准确的遗传HD基因敲入小鼠模型中进行扩展。在本研究中，我们将进行实验，以深入 在许多基本水平上询问这些修饰基因。在目标1中，我们将使用遗传实验 以测试改变体细胞扩增对疾病表达的影响。在目标2中，我们将 在患者细胞和小鼠模型中进行生物化学研究，以了解作用机制， 功能性后果是人类修饰变体。在目标3中，我们将研究人类修饰剂的影响 CAG不稳定性和大脑中特定细胞类型的基因表达的变化。所有这些 由人类基因数据驱动的实验将为疾病机制提供重要的见解 在HD中的修饰，并将指导靶向CAG扩增的治疗剂的开发。

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.