Integrating Quality Control: Studies of CHIP in Age-related Neurodegeneration

摘要 随着人类寿命的延长，年龄相关的神经退行性疾病由 异常蛋白质的积累正变得越来越普遍。在所有单元格中， 蛋白质质量控制网络(PQC)的存在是为了“处理”这些异常蛋白质的出现 来自突变、环境应激源或衰老过程。选择性大脑 然而，与年龄相关的神经退行性疾病的脆弱性表明 大脑中PQC的一些独特之处使这个器官特别容易受到影响 到错误折叠的蛋白质。不幸的是，哪些PQC组件在 大脑以及这些成分在暴露于异常蛋白质时的反应 未知。这里提出的研究将系统地探索PQC的变化 当易于聚集的蛋白在大脑中表达时发生，并将定义 一种关键的PQC泛素连接酶CHIP如何处理神经退行性变 疾病蛋白。潜在的假设有两个：1)大脑中的PQC未能保持 在与年龄相关的神经退行性变过程中蛋白毒性应激增加的速度；以及2) 大脑对蛋白毒性应激的PQC反应严重依赖于一种多功能的芯片 调节伴侣依赖和泛素依赖途径之间的串扰的蛋白质。 在三个目标上，建立在研究人员在聚谷氨酰胺方面的专业知识 神经退行性变和泛素连接酶生物学，我们将使用互补的遗传和 生化技术定位衰老小鼠基础和适应性PQC的变化 在大脑和小鼠的多谷氨酰胺神经退行性疾病模型中， 芯片的存在和缺失。其他研究将通过以下方式确定这些机制 哪些芯片连接酶复合体在大脑中受到调控。拟议的研究将确定 作用于中枢神经系统异常折叠蛋白的关键PQC组件，并提供 对他们的行动机制的洞察。预计这一结果将为 广泛的年龄相关神经退行性疾病的治疗策略。

Abstract As humans live longer, age-related neurodegenerative disorders caused by the accumulation of abnormal proteins are becoming increasingly common. In all cells, a protein quality control network (PQC) exists to "handle" such abnormal proteins arising from mutations, environmental stressors or the aging process. The selective brain vulnerability in age-related neurodegenerative disorders, however, suggests there is something unique about PQC in the brain that makes this organ particularly susceptible to misfolded proteins. Unfortunately, which PQC components are most important in the brain and how these components respond when exposed to abnormal proteins remain unknown. The studies proposed here will systematically explore changes in PQC that occur when aggregation-prone proteins are expressed in brain and will define mechanistically how a key PQC ubiquitin ligase, CHIP, handles neurodegenerative disease proteins. The underlying hypothesis is twofold: 1) PQC in the brain fails to keep pace with mounting proteotoxic stress during age-related neurodegeneration; and 2) the brain's PQC response to proteotoxic stress relies heavily on CHIP, a multifunctional protein that mediates crosstalk between chaperone- and ubiquitin-dependent pathways. In three Aims that build off the investigators' expertise in polyglutamine neurodegeneration and ubiquitin ligase biology, we will use complementary genetic and biochemical techniques to map basal and adaptive PQC changes in the aging mouse brain and in mouse models of polyglutamine neurodegenerative disease, both in the presence and absence of CHIP. Additional studies will determine the mechanisms by which CHIP ligase complexes are regulated in brain. The proposed studies will identify key PQC components that act on abnormally folded protein in the CNS and provide insights into their mechanisms of action. The results are expected to suggest targets for therapeutic strategies in a wide range of age-related neurodegenerative disorders.