Mechanisms of neurodegenerative diseases: intersections with ubiquitin pathways

这项R35提案建立在首席研究员长期以来成功寻找年龄原因的基础上- 相关的神经退行性疾病和发展治疗这些毁灭性的， 紊乱该提案的统一主题是关注参与泛素相关质量控制的蛋白质 在神经退行性疾病中，它们倾向于相分离和聚集。基础上 我们最近在多聚谷氨酰胺介导的神经变性和脑表达的泛素（一类 涉及各种神经退行性疾病的蛋白质），我们将应用多标量方法来定义 致病机制，强调在寻找新的 治疗目标泛素在神经系统中的重要性远远超出了其经典的 在泛素-蛋白酶体系统中具有明确的降解作用。但是更广泛的泛素信号系统 由神经系统疾病损害或响应于神经系统疾病而被激活的神经系统疾病代表了目前神经系统疾病的显著差距。 知识利用广泛的创新工具/模型和卓越的研究环境，我们 将解决与年龄相关的神经退行性变广泛相关的基本问题。这些热点问题 包括：改变泛素信号在细胞核中的影响;改变泛素的贡献 选择性细胞类型和区域脆弱性的内稳态;以及突变诱导的 疾病蛋白进行的相变的变化，泛素连接途径的功能改变， 神经系统的毒性。我们通过R35所做的发现将有助于定义复杂的 泛素在神经系统疾病中的生物学作用，突出了疾病的潜在共同因素 发病机制，并确定有前途的治疗目标，可以推动治疗的发展， 神经退行性疾病

This R35 proposal builds on the principal investigator’s longstanding success seeking the causes of age- related neurodegenerative diseases and developing treatments for these devastating and largely fatal disorders. The proposal’s unifying theme is a focus on proteins that participate in ubiquitin-linked quality control pathways and that are prone, in neurodegenerative diseases, to phase-separate and aggregate. Building on our recent discoveries in polyglutamine-mediated neurodegeneration and brain-expressed ubiquilins (a class of proteins implicated in various neurodegenerative diseases), we will apply multi-scalar approaches to define pathogenic mechanisms, emphasizing intersections with ubiquitin-dependent pathways in the search for novel therapeutic targets. The importance of ubiquitin in the nervous system extends far beyond its classically defined degradative role in the ubiquitin-proteasome system. But how the broader ubiquitin signaling system is impaired by, or activated in response to, diseases of the nervous system represents a significant gap in current knowledge. Leveraging a broad suite of innovative tools/models and an exceptional research environment, we will address fundamental issues of broad relevance to age-related neurodegeneration. These topical issues include: the impact of altered ubiquitin signaling in the nucleus; the contribution of altered ubiquitin homeostasis to selective cell type and regional vulnerability; and the relationship between mutation-induced changes in phase transitions undertaken by disease proteins, altered function in ubiquitin-linked pathways, and toxicity in the nervous system. The discoveries we make through the R35 will help define the complex biological roles of ubiquitin in diseases of the nervous system, highlight potential shared elements of disease pathogenesis, and identify promising therapeutic targets that could drive the development of treatments for neurodegenerative disorders.