Histone deacetylase 6 and aggresome-associated neurodegeneration

描述（由申请人提供）：本提案的长期目标是阐明有毒蛋白聚集体加工的关键细胞机制及其在神经退行性疾病发病机制中的作用。蛋白质聚集到一个特殊的包涵体，即聚集体的浓度，已经成为错误折叠蛋白质病理积累的关键细胞反应。聚合体的临床相关性与路易体的惊人相似性有关，路易体是帕金森病和其他神经退行性疾病的病理组织学标志。我们已经发现微管相关的去乙酰化酶HDAC6是路易小体的一个组成部分，在聚集体的形成中起着关键作用。HDAC6的缺失导致聚集体形成失败和明显的细胞死亡，以响应错误折叠的蛋白质积累。我们假设HDAC6通过识别和促进泛素化蛋白聚集体向聚集体/路易小体的运输来保护神经元，从而防止有毒蛋白聚集体引起的神经退行性变。我们建议：目标1。描述HDAC6复合物在泛素依赖性错误折叠蛋白加工中的功能。我们将表征HDAC6复合物的泛素结合活性，并确定多泛素修饰在错误折叠蛋白加工和聚集体形成中的性质和功能。目标2。表征hdac6介导的去乙酰化在错误折叠蛋白加工和聚集体形成中的作用。我们将确定蛋白质乙酰化如何调节错误折叠蛋白泛素连接酶CHIP的功能以及微管网络对错误折叠蛋白的转运。目标3。目的探讨HDAC6在帕金森病发病机制中的作用。我们将确定HDAC6基因敲除小鼠是否在形成路易小体方面存在缺陷，并且在对帕金森诱导的突变a-突触核蛋白表达的反应中更容易发生神经变性。毒性蛋白聚集体的积累已成为神经退行性疾病的常见原因。通过表征消除有毒蛋白聚集体的机制和蛋白质机制，我们希望为开发治疗神经退行性疾病的新治疗方法找到新的途径。

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to elucidate the cellular machinery critical for the processing of toxic protein aggregates and its role in the pathogenesis of neurodegenerative disease. The cocentration of protein aggregates to a specialized inclusion body, the aggresome, has emerged as a critical cellular response to the pathological accumulation of misfolded proteins. The clinical relevance of aggresomes is implicated by its striking similarity to Lewy bodies, the pathohistological hallmark of Parkinson's and other neurodegenerative diseases. We have discoverd that the microtubule-associated deacetylase HDAC6 is a componet of Lewy bodies and plays a critical role in aggresome formation. Loss of HDAC6 results in a failure in aggresome formation and pronounced cell death in response to misfolded protein accumulation. We hypothesize that HDAC6 protects neurons by recognizing and facilitating the transport of ubiquitinated protein aggregates to aggresomes/Lewy bodies, thereby preventing neurodegeneration caused by toxic protein aggregates. We propose: Aim 1. To delineate the function of the HDAC6 complex in ubiquitin-dependent misfolded protein processing. We will characterize the ubiquitin-binding activity of HDAC6 complex and determine the nature and functions of poly-ubiquitin modification in misfolded protein processing and aggresome formation. Aim 2. To characterize the role of HDAC6-mediated deacetylation in misfolded protein processing and aggresome formation. We will determine how protein acetylation regulates the function of the misfolded protein ubiquitin ligase CHIP and the transport of misfolded proteins by the microtubule network. Aim 3. To characterize the role of HDAC6 in the pathogenesis of Parkinson's disease. We will determine whether HDAC6 knockout mice are defective in forming Lewy bodies and more susceptible to neurodegeneration in response to Parkinsonism-inducing mutant a-synuclein expression. The accumulation of toxic protein aggregates has emerged as a common cause of neurodegenerative diseases. By characterizing the mechanism and protein machinery that eliminate toxic protein aggregates, we hope to identify new avenues for developing novel therapeutic approaches for treating neurodegenerative disease.