Molecular Mechanisms Underlying Cell Type-Specific Vulnerability in Huntington’s Disease

摘要 最常见的神经退行性疾病，包括阿尔茨海默氏症、帕金森氏症和亨廷顿氏症 所有疾病都有不同的临床表现。这些不同的临床表现的基础是 在每种疾病中，特定神经元细胞类型对死亡或功能障碍的脆弱性增强， 疾病相关基因的广泛表达。我的工作使用创新的方法来解决这些问题 长期存在的脆弱性加剧问题，这些问题在2005年仍然是实地的未决问题， 几十年我主要参与开发了一种广泛使用的细胞类型特异性分析方法， 翻译核糖体亲和纯化（TRAP），其允许细胞类型特异性RNA分析。我的实验室最近 开发了一种新的中枢神经系统体内遗传筛选平台，这是一种强大的大脑研究新方法， 它允许系统地测试基因组中每个基因对疾病的因果效应（相对于相关性）， 表型，而不是更标准的方法，测试每个动物的单个基因。此外，使用 单细胞测序方法，我们还进行了最大的单细胞研究的亨廷顿的 迄今为止进行的患者组织检查。这些研究共同揭示了转录的范围， 在亨廷顿氏病和亨廷顿氏病模型组织中， 神经元先天免疫激活可能是亨廷顿舞蹈病细胞类型特异性脆弱性的关键驱动因素 疾病我的长期研究目标，从亨廷顿病作为一种典型疾病开始，是阐明 增强神经退行性疾病脆弱性的基础，不仅是发现有价值的 深入了解疾病相关神经元细胞类型的细胞生物学，同时也确定新的治疗方法， 目标的

Abstract The most common neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, all display distinct clinical presentations. The basis of these distinct clinical presentations is the enhanced vulnerability of specific neuronal cell types to death or dysfunction in each disease, despite widespread expression of disease-associated genes. My work uses innovative approaches to address these long-standing questions of enhanced vulnerability, which have remained open questions in the field for decades. I was centrally involved in developing a widely used cell type-specific profiling methodology known as translating ribosome affinity purification (TRAP) that allows cell type-specific RNA profiling. My lab has recently developed a new genetic in vivo screening platform for the CNS, a powerful new approach for brain studies as it allows for systematically testing the causal effect (versus correlation) of each gene in the genome for disease phenotypes, rather than more standard approaches that test a single gene per animal. Additionally, using single cell sequencing approaches, we have also conducted the largest single cell studies of Huntington’s disease patient tissue conducted to date. These studies have collectively revealed the scope of transcriptional dysregulation in Huntington’s disease and Huntington’s disease model tissue, and also have implicated neuronal innate immune activation as a likely key driver of cell type-specific vulnerability in Huntington’s disease. My long-term research goal, starting with Huntington’s disease as a model disorder, is to elucidate the basis of enhanced vulnerability in neurodegenerative disease, not only as a window for discovering valuable insights into the cell biology of disease-relevant neuronal cell types, but also identifying new therapeutic targets.