Mechanisms of neurodegenerative diseases: intersections with ubiquitin pathways

这项R35提案建立在首席调查员长期成功地寻找年龄原因的基础上- 相关的神经退行性疾病和正在开发的治疗这些破坏性和大部分致命的 精神错乱。该提案的统一主题是关注参与泛素连接的质量控制的蛋白质 在神经退行性疾病中，容易出现阶段分离和聚集的通路。在基础上建设 我们最近在多谷氨酰胺介导的神经退行性变和脑表达的泛素(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，在寻找新的致病机制时强调与泛素依赖途径的交叉 治疗靶点。泛素在神经系统中的重要性远远超出了它的经典意义 泛素-蛋白酶体系统中明确的降解作用。但更广泛的泛素信号系统是如何 神经系统疾病的损害或激活代表着电流的显著差距 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：核内泛素信号变化的影响；泛素变化的贡献 对选择性细胞类型的动态平衡和区域易损性；以及突变诱导的关系 疾病蛋白进行的相变，泛素连接途径中功能的改变，以及 神经系统中的毒性。我们通过R35所做的发现将有助于定义该综合体 泛素在神经系统疾病中的生物学作用，突出疾病的潜在共同要素 发病机制，并确定有希望的治疗靶点，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.