Histone deacetylase 6 and aggresome-associated neurodegeneration

描述（由申请方提供）：本提案的长期目标是阐明对毒性蛋白质聚集体加工至关重要的细胞机制及其在神经退行性疾病发病机制中的作用。蛋白质聚集体的浓缩到一个专门的包涵体，侵略者，已经成为一个重要的细胞反应的病理积累的错误折叠的蛋白质。侵袭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。我们已经证实微管相关的脱乙酰酶HDAC 6是Lewy小体的一个组成部分，并在侵略体的形成中起着关键作用。HDAC 6的缺失导致攻击基因组形成失败，并响应于错误折叠的蛋白质积累而导致明显的细胞死亡。我们假设HDAC 6通过识别和促进泛素化蛋白聚集体转运到攻击体/路易体来保护神经元，从而防止由有毒蛋白聚集体引起的神经变性。我们建议：描述HDAC 6复合物在泛素依赖性错误折叠蛋白质加工中的功能。我们将表征HDAC 6复合物的泛素结合活性，并确定多聚泛素修饰在错误折叠蛋白质加工和侵略体形成中的性质和功能。目标二。表征HDAC 6介导的去乙酰化在错误折叠的蛋白质加工和攻击体形成中的作用。我们将确定蛋白质乙酰化如何调节错误折叠的蛋白质泛素连接酶CHIP的功能和错误折叠的蛋白质的微管网络的运输。目标3。研究HDAC 6在帕金森病发病机制中的作用。我们将确定HDAC 6基因敲除小鼠是否在形成路易体方面有缺陷，并且是否更容易响应于帕金森病诱导的突变体α-突触核蛋白表达而发生神经变性。毒性蛋白质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质聚集体的机制和蛋白质机制，我们希望确定开发治疗神经退行性疾病的新治疗方法的新途径。

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.