Histone deacetylase 6 and aggresome-associated neurodegeneration

这项建议的长期目标是阐明细胞机制对处理 毒性蛋白聚集体及其在神经退行性疾病发病机制中的作用。的集中度 蛋白质聚集成一个特殊的包涵体，侵袭体，已经成为一种关键的细胞 对错误折叠的蛋白质的病理性堆积的反应。侵袭体的临床相关性是 因其与路易小体惊人的相似性而牵连，帕金森和其他疾病的病理组织学特征 神经退行性疾病。我们发现微管相关脱乙酰酶HDAC6是一种 是路易体的组成部分，在侵袭体的形成中起着关键作用。HDAC6丢失会导致故障 在侵袭体的形成和显著的细胞死亡，以回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的转运来保护神经元 蛋白质聚集到侵袭体/刘易体，从而防止有毒物质引起的神经变性 蛋白质聚集体。我们建议： 目的1.研究HDAC6复合体在泛素依赖的错折叠蛋白加工中的作用。 我们将表征HDAC6复合体的泛素结合活性，并确定其性质和功能 多泛素修饰在错误折叠的蛋白质加工和侵袭体形成中的作用。 目的2.研究HDAC6介导的脱乙酰基在错误折叠蛋白质加工中的作用。 攻击性的队形。我们将确定蛋白质乙酰化如何调节错误折叠的功能- 蛋白质泛素连接酶芯片和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。我们将决定 HDAC6基因敲除小鼠是否在形成路易小体方面存在缺陷，并更容易患上 帕金森病诱导突变型α-突触核蛋白表达引起的神经变性。 有毒蛋白质聚集物的积累已成为神经退行性变的常见原因。 疾病。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变的新的治疗方法。 疾病。

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 charaterize 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 determinie 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.