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

描述（由申请人提供）：随着人类寿命的延长，由异常蛋白质积累引起的与年龄相关的神经退行性疾病变得越来越常见。在所有细胞中，存在蛋白质质量控制网络（PQC）来“处理”由突变，环境压力或老化过程引起的异常蛋白质。然而，与年龄相关的神经退行性疾病中的选择性大脑脆弱性表明，大脑中PQC有一些独特的东西，使这个器官特别容易受到错误折叠蛋白的影响。不幸的是，哪些PQC成分在大脑中最重要，以及这些成分在暴露于异常蛋白质时如何反应仍然未知。本文提出的研究将系统地探索当易聚集蛋白在大脑中表达时发生的PQC变化，并将机械地定义关键PQC泛素连接酶CHIP如何处理神经退行性疾病蛋白。潜在的假设是双重的：1）在年龄相关的神经变性期间，大脑中的PQC未能跟上不断增加的蛋白毒性应激;以及2）大脑对蛋白毒性应激的PQC响应严重依赖于CHIP，CHIP是一种多功能蛋白，其介导伴侣蛋白和泛素依赖性通路之间的串扰。在三个目标，建立了研究人员在多聚谷氨酰胺神经变性和泛素连接酶生物学的专业知识，我们将使用互补的遗传和生物化学技术来映射基础和适应性PQC的变化，在衰老小鼠大脑和小鼠模型的多聚谷氨酰胺神经变性疾病，无论是在存在和不存在CHIP。进一步的研究将确定CHIP连接酶复合物在脑中调节的机制。拟议的研究将确定作用于CNS中异常折叠蛋白质的关键PQC组分，并提供对其作用机制的见解。这些结果有望为广泛的年龄相关神经退行性疾病的治疗策略提供靶点。公共卫生相关性：随着年龄的增长，许多常见的无法治愈的脑部疾病都与大脑中异常的蛋白质沉积有关。该提案旨在理解和定义脑细胞内抵消这些异常蛋白质的“质量控制”机制。了解这一机制可能会为随着年龄增长而发生的大量散发性和遗传性神经退行性疾病提供治疗途径。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Many common, incurable brain diseases that develop as people get older are associated with abnormal protein deposits in the brain. This proposal seeks to understand and define the "quality control" machinery inside brain cells that counteracts these abnormal proteins. Understanding this machinery may suggest routes to therapy for a large range of sporadic and hereditary neurodegenerative diseases that occur as we age.