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，由异常蛋白积累引起的与年龄相关的神经退行性疾病变得越来越普遍。在所有细胞中，都存在一个蛋白质质量控制网络（PQC）来“处理”由突变、环境压力或衰老过程引起的异常蛋白质。然而，在与年龄相关的神经退行性疾病中，大脑的选择性脆弱性表明，大脑中的PQC有一些独特之处，使这个器官特别容易受到错误折叠蛋白质的影响。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。这里提出的研究将系统地探索当易于聚集的蛋白在大脑中表达时PQC发生的变化，并将从机制上定义关键的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)在与年龄相关的神经变性过程中，大脑中的PQC无法跟上不断增加的蛋白质毒性应激；2)大脑对蛋白质毒性应激的PQC反应严重依赖CHIP， CHIP是一种介导伴侣蛋白和泛素依赖通路之间串扰的多功能蛋白。基于研究者在聚谷氨酰胺神经变性和泛素连接酶生物学方面的专业知识，在三个目标中，我们将使用互补的遗传和生化技术来绘制衰老小鼠大脑和聚谷氨酰胺神经退行性疾病小鼠模型中存在和不存在CHIP的基础和适应性PQC变化。进一步的研究将确定CHIP连接酶复合物在大脑中的调节机制。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成分，并提供对其作用机制的见解。该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：随着人们年龄的增长，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。这项提议试图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的治疗提供途径。

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.