Histone deacetylase 6 and aggresome-associated neurodegeneration

描述(由申请人提供)：这项建议的长期目标是阐明处理有毒蛋白质聚集体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。蛋白质聚集体聚集到一个特殊的包涵体，侵袭体，已经成为错误折叠蛋白质病理性积累的关键细胞反应。侵袭体的临床相关性是因为它与路易体有着惊人的相似性，路易体是帕金森氏症和其他神经退行性疾病的病理组织学标志。我们发现微管相关脱乙酰酶HDAC6是路易小体的组成部分，在侵袭体的形成中起着关键作用。HDAC6的缺失会导致侵袭体的形成失败，并导致错误折叠的蛋白质积累导致细胞死亡。我们假设HDAC6通过识别和促进泛素化蛋白聚集体向侵袭体/刘易体的运输来保护神经元，从而防止有毒蛋白质聚集体引起的神经变性。我们提出：目的1.阐明HDAC6复合体在泛素依赖的错误折叠蛋白加工中的功能。我们将表征HDAC6复合体的泛素结合活性，并确定多泛素修饰在错误折叠的蛋白质加工和侵袭体形成中的性质和功能。目的2.研究HDAC6介导的脱乙酰基在错误折叠蛋白加工和侵袭体形成中的作用。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芯片的功能，以及错误折叠的蛋白质通过微管网络的运输。目的3.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，以及是否更容易对帕金森病诱导突变的α-突触核蛋白表达做出神经退变的反应。有毒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，我们希望找到新的途径来开发治疗神经退行性疾病的新的治疗方法。

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.