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

摘要 随着人类寿命的延长，与年龄相关的神经退行性疾病， 异常蛋白质的积累变得越来越普遍。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”这种异常蛋白质， 基因突变、环境压力或衰老过程中产生的。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， PQC在大脑中的独特之处使得这个器官特别容易受到 错误折叠的蛋白质。不幸的是，PQC组件中最重要的是 大脑以及这些成分在暴露于异常蛋白质时的反应仍然存在 未知本文提出的研究将系统地探讨PQC的变化， 当聚集倾向蛋白在大脑中表达时发生， 关键的PQC泛素连接酶CHIP如何机械地处理神经退行性疾病 疾病蛋白质潜在的假设是双重的：1）大脑中的PQC未能保持 与年龄相关的神经退行性变过程中不断增加的蛋白毒性应激同步;和2） 大脑对蛋白毒性应激的PQC反应在很大程度上依赖于CHIP，一种多功能的 介导伴侣蛋白和泛素依赖途径之间相互干扰的蛋白质。 在三个目标，建立了研究人员的专业知识，在聚谷氨酰胺 神经变性和泛素连接酶生物学，我们将使用互补的遗传和 生物化学技术绘制衰老小鼠的基础和适应性PQC变化 在多聚谷氨酰胺神经退行性疾病的小鼠模型中， 有无CHIP进一步的研究将确定机制， 其中CHIP连接酶复合物在脑中受到调节。拟议的研究将确定 作用于CNS中异常折叠蛋白质并提供 深入了解其作用机制。预计结果将提出以下目标： 在广泛的年龄相关的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.