Molecular Mechanisms of Pathogenesis in Huntington’s disease

亨廷顿氏病（HD）是遗传原因引起的第一种神经退行性疾病之一， 是一种遗传性神经退行性疾病， 治疗HD是由编码多聚谷氨酰胺的HTT基因中的CAG重复扩增引起的 在亨廷顿蛋白（HTT）的氨基末端部分内的（polyQ）区。虽然该领域已经获得了 尽管我们对HD中被破坏的许多细胞过程的了解，我们还不了解 关键近端HD相关事件之间的相互作用，例如 特异性细胞中异常突变HTT（mHTT）积累、RNA生物学和表观遗传事件 大脑中的类型。同样，我们不知道这些过程的变化如何影响临床 疾病的表现，最好的治疗干预和什么结果的措施 可能是HD模型中最具信息性的。这里提出的研究的首要重点是 是填补我们关于这些因素如何影响HD发病和进展的知识的重要空白 以及这种理解如何可能导致新的疾病改变疗法。拟议研究 我将利用我的实验室和我的合作者开发的独特资源和方法 并将利用最先进的技术，如单细胞RNA-seq，质谱和 冷冻电子断层扫描来剖析分子机制最终，治疗方法 疾病，包括联合治疗，可能需要一个更好的基础， 了解mHTT如何导致HD病理和死亡。我们最近的数据显示 蛋白质翻译后修饰（PTM）途径之间的意想不到的关系， 异常突变HTT的积累和DNA损伤反应的神经元，后者现在 被认为是HD发病年龄的关键调节剂。使用系统生物学方法，我们 了解mHTT的慢性表达和积累如何影响基因表达， 寻求对RNA生物学和因果网络的更全面的理解， 特定细胞类型。在这里，我建议进行调查，以解决我们在这方面的主要差距。 了解基本的分子和细胞事件是如何构成突变型HD的基础的。 一种基因导致大脑中特定细胞群的退化，从而诱导运动和认知能力。 最终导致患者过早死亡。我的项目得益于 患者iPSC和HD小鼠模型以及我们广泛而富有成效的合作 成立多年。总体目标是了解近端和起始事件 在疾病和开发治疗HD，我建议两个主要的研究途径 涉及HD中1）蛋白质稳态和2）表观遗传学和RNA生物学的整合。

Huntington’s disease (HD), one of the first neurodegenerative diseases for which a genetic cause was determined, is an inherited neurodegenerative disorder that has no disease-modifying treatment. HD is caused by a CAG repeat expansion in the HTT gene encoding a polyglutamine (polyQ) tract within the amino terminal portion of Huntingtin (HTT). While the field has gained an understanding of the many cellular processes that are disrupted in HD, we do not yet understand the interplay between key proximal HD-associated events, such as the relationship between aberrant mutant HTT (mHTT) accumulation, RNA biology and epigenetic events in specific cell types in the brain. Similarly, we do not know how changes in these processes impact clinical manifestation of disease, where best to intervene therapeutically and what outcome measures may be the most informative in HD models. The overarching focus of the research proposed here is to fill vital gaps in our knowledge about how these factors impact onset and progression of HD and how that understanding might lead to new disease-altering therapies. The proposed research will leverage unique resources and methods developed in my lab and those of my collaborators and will utilize state-of-the-art technologies such as single-cell RNA-seq, mass spectrometry and cryo-electron tomography to dissect molecular mechanisms. Ultimately, treatments for this disease, including combination therapies, will likely require a much better fundamental understanding of how mHTT leads to HD pathology and death. Our recent data suggests unexpected relationships between protein posttranslational modification (PTM) pathways, aberrant mutant HTT accumulation and DNA damage responses in neurons, the latter now implicated as a critical modifier of HD age-of-onset. Using a systems biology approach we are learning how chronic expression and accumulation of mHTT impacts gene expression and now seek to develop a more comprehensive understanding of RNA biology and causal networks in specific cell types. Here I propose investigations aimed at addressing major gaps in our understanding of how the fundamental molecular and cellular events underlie how the mutant HD gene causes degeneration of specific cell populations in the brain to induce motor and cognitive decline and ultimately premature death of patients. My program benefits from the integrated use of patient iPSCs and HD mouse models and the extensive and productive collaborations we have established over many years. With the overall goal of understanding proximal and initiating events in the disease and developing therapies for HD, I propose two primary avenues of research relating to the integration of 1) protein homeostasis and 2) epigenetics and RNA biology in HD.