Molecular Mechanisms of Pathogenesis in Huntington’s disease

亨廷顿病(HD)，是首批由遗传原因引起的神经退行性疾病之一 是一种遗传性神经退行性疾病，没有疾病修饰作用 治疗。HD是由编码聚谷氨酰胺的HTT基因CAG重复扩增引起的 (PolyQ)亨廷顿(HTT)氨基末端部分内的区域。虽然该领域已经获得了 对HD中被破坏的许多细胞过程的了解，我们还不清楚 关键近端HD相关事件之间的相互作用，例如 突变型HTT(MHTT)在特定细胞中的异常积累、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中的变化如何影响临床 疾病的表现，在哪里进行最好的治疗干预，以及什么结果衡量 可能是高清机型中信息量最大的。这里提出的研究的主要重点是 填补我们关于这些因素如何影响HD发病和进展的重要知识空白 以及这种理解可能会如何导致新的改变疾病的疗法。拟议的研究 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，质谱仪和 冷冻电子断层扫描，以剖析分子机制。归根结底，对此的治疗 疾病，包括联合疗法，可能需要更好的基础 了解mHTT是如何导致HD病理和死亡的。我们最近的数据表明 蛋白质翻译后修饰(PTM)途径之间意想不到的关系， 突变型HTT在神经元中的异常蓄积和DNA损伤反应，后者现在 被认为是HD发病年龄的关键修饰物。使用系统生物学方法，我们正在 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 特定的细胞类型。在这里，我建议进行调查，旨在解决我们在 了解基本的分子和细胞事件是如何导致突变的HD 基因导致大脑中特定细胞群的退化，以诱导运动和认知 下降，最终导致患者过早死亡。我的程序从综合使用中受益 患者ipscs和HD鼠标模型，以及我们拥有的广泛和富有成效的合作 经过多年的建立。总体目标是了解邻近事件和启动事件 在疾病和开发HD治疗方法方面，我提出了两个主要的研究途径 与HD中1)蛋白质动态平衡和2)表观遗传学和RNA生物学的整合有关。

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.