Histone deacetylase 6 and aggresome-associated neurodegeneration

该提案的长期目标是阐明对于加工至关重要的细胞机制 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。的浓度 蛋白质聚集到一个专门的包涵体，侵略者，已经成为一个关键的细胞 对错误折叠蛋白质病理性积累的反应。侵袭体的临床相关性是 它与路易体惊人的相似性暗示，路易体是帕金森病和其他疾病的病理组织学标志。 神经退行性疾病我们已经证实，微管相关脱乙酰酶HDAC 6是一种 它是路易体的重要组成部分，在侵略形成中起着关键作用。HDAC 6丢失导致故障 在攻击体形成和显著的细胞死亡中响应于错误折叠的蛋白质积累。我们 假设HDAC 6通过识别和促进泛素化的转运来保护神经元， 蛋白质聚集到攻击体/路易体，从而防止由毒性引起的神经变性。 蛋白质聚集体。我们建议： 目标1。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。 我们将对HDAC 6复合物的泛素结合活性进行表征，并确定其性质和功能 在错误折叠的蛋白质加工和侵略形成中的多聚泛素修饰。 目标2.为了表征HDAC 6介导的去乙酰化在错误折叠的蛋白质加工中的作用， 攻击性队形。我们将确定蛋白质乙酰化如何调节错误折叠的功能- 蛋白泛素连接酶CHIP和微管网络对错误折叠蛋白的转运。 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， 神经变性对帕金森氏症诱导的突变体α-突触核蛋白表达的响应。 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。 疾病通过表征消除有毒蛋白质聚集体的机制和蛋白质机器， 我们希望找到新的途径来开发治疗神经退行性疾病的新方法， 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.