Histone deacetylase 6 and aggresome-associated neurodegeneration

组蛋白脱乙酰酶 6 和攻击体相关的神经变性

基本信息

批准号：
7166814
负责人：
TSO-PANG YAO
金额：
$ 34.03万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-04 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7166814
关键词：
Acetylation Address Binding Biogenesis Cell Death Cells Clinical Code Complex Deacetylase Deacetylation Dynein ATPase Employee Strikes Excision Failure HDAC6 gene Inclusion Bodies Knockout Mice Lewy Bodies Link Lysine Mediating Microtubule Proteins Microtubule-Organizing Center Microtubules Modification Molecular Molecular Chaperones Motor Nature Nerve Degeneration Neurodegenerative Disorders Neurons Parkinson Disease Parkinsonian Disorders Pathogenesis Pathway interactions Physiological Play Polyubiquitin Polyubiquitination Process Protein Acetylation Proteins Research Personnel Role Specificity Stress-Induced Protein Testing Transport Process Tubulin Ubiquitin Ubiquitin-Protein Ligase Complexes Ubiquitination base clinically relevant histone deacetylase 6 mouse model mutant neuron loss novel novel therapeutics prevent programs protein aggregate protein misfolding response synuclein ubiquitin-protein ligase

项目摘要

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.

描述（由申请人提供）：该提案的长期目标是阐明对有毒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。蛋白质聚集到一种特殊的包涵体，即聚集体，已成为对错误折叠蛋白质病理性积累的关键细胞反应。攻击体的临床意义在于其与路易体的惊人相似性，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。我们发现微管相关脱乙酰酶 HDAC6 是路易体的组成部分，在聚集体形成中发挥着关键作用。 HDAC6 的缺失会导致攻击体形成失败，并因错误折叠的蛋白质积累而导致明显的细胞死亡。我们假设 HDAC6 通过识别和促进泛素化蛋白聚集体转运至聚集体/路易体来保护神经元，从而防止有毒蛋白聚集体引起的神经变性。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质加工中的功能。我们将表征 HDAC6 复合物的泛素结合活性，并确定多聚泛素修饰在错误折叠蛋白质加工和聚集体形成中的性质和功能。目标 2. 表征 HDAC6 介导的脱乙酰化在错误折叠的蛋白质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质泛素连接酶 CHIP 的功能以及微管网络对错误折叠蛋白质的运输。目标 3. 表征 HDAC6 在帕金森病发病机制中的作用。我们将确定 HDAC6 敲除小鼠是否在形成路易体方面存在缺陷，并且更容易因帕金森病诱导的突变型 α-突触核蛋白表达而发生神经变性。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，我们希望找到开发治疗神经退行性疾病的新治疗方法的新途径。