UBIQUITINATED PROTEIN DEGRADATION & NEURODEGENERATION

泛素化蛋白质降解

• 批准号: 6454900
• 负责人: MARIA Emilia FIGUEIREDO-PEREIRA
• 金额: $ 5万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6454900
• 关键词: active sites; cell line; chemical aggregate; chemical conjugate; endopeptidases; enzyme activity; enzyme complex; enzyme inhibitors; gene mutation; genetic regulation; hypoxia; inclusion body; neural degeneration; neurofibrillary tangles; oxidative stress; protein degradation; protein structure function; stress proteins; tau proteins; ubiquitin

DESCRIPTION: (From the applicant's abstract): Inclusions containing ubiquitinated proteins are a hallmark of many neurological disorders such as Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases. Covalent binding of ubiquitin to proteins is known to mark them for degradation by the ubiquitin/proteasome pathway. This ATP-dependent pathway plays a major role in the breakdown of abnormal proteins, which should be rapidly removed. Although the relationship between accumulation of ubiquitinated proteins and neurodegeneration is poorly understood, recently identified mutations in ubiquitin and in an enzyme of the ubiquitin/proteasome pathway were found to be closely associated with sporadic AD and familial PD, respectively. We propose that ubiquitin-protein aggregates must result from a malfunction or overload of the ubiquitin/proteasome pathway or from structural changes in protein substrates halting their degradation, and that failure to eliminate ubiquitinated proteins disrupts cellular homeostasis contributing to degeneration. Therefore, it is of the utmost importance to identify stress conditions that jeopardize the functioning of the ubiquitin/proteasome pathway and lead to accumulation of ubiquitinated proteins in neuronal cells. The goals of this project are: (i) to identify stress conditions that interfere with the proper functioning of the ubiquitin/proteasome pathway and understand the biochemical mechanisms by which they disrupt homeostasis; (ii) to study genetic regulatory pathways affected by these conditions and establish how they change expression of enzymes of the ubiquitin/proteasome pathway as well as of related proteins involved in the pathological process; (iii) test the therapeutic effectiveness of antioxidants and inhibitors o some of these regulatory pathways, in preventing accumulation of ubiquitinated proteins and neurodegeneration. To better understand the role played by the ubiquitin/proteasome pathway in neurodegeneration we will establish a stable neuronal cell line in which the activity of its proteolytic moiety, the 20S proteasome, is compromised by a mutation in the active site of one of its catalytic subunits. The proposed studies will yield insights into a poorly understood aspect of neurodegeneration, and more specifically identify novel therapeutic targets for prevention of the accumulation of ubiquitinated proteins in stressed neuronal cells.

描述：（来自申请人的摘要）：包含 泛素化蛋白是许多神经系统疾病的标志， 阿尔茨海默氏症（AD）、帕金森氏症（PD）和亨廷顿氏病。共价结合 已知泛素与蛋白质的结合可以标记它们的降解， 泛素/蛋白酶体途径。这种ATP依赖性途径在以下方面起着重要作用： 异常蛋白质的分解，应迅速清除。虽然 泛素化蛋白的积累与 人们对神经退行性疾病的了解甚少，最近发现了神经退行性疾病的突变， 泛素和泛素/蛋白酶体途径的酶被发现是 分别与散发性AD和家族性PD密切相关。我们提出 泛素-蛋白质聚集体一定是由于 泛素/蛋白酶体途径或蛋白质结构变化 基质停止其降解，以及未能消除 泛素化蛋白质破坏细胞内稳态， 退化因此，识别压力是至关重要的 危及遍在蛋白/蛋白酶体途径功能的情况 并导致泛素化蛋白在神经元细胞中的积累。的目标 （一）确定干扰本项目的应力条件; 泛素/蛋白酶体通路的正常功能，并了解 生物化学机制，他们破坏稳态;（ii）研究遗传 受这些条件影响的调节途径，并确定它们如何变化 表达泛素/蛋白酶体途径的酶以及相关的 参与病理过程的蛋白质;（iii）测试治疗性 抗氧化剂和抑制剂对这些调节性 途径，防止泛素化蛋白的积累， 神经变性为了更好地理解 泛素/蛋白酶体通路在神经变性中的作用，我们将建立一个稳定的 神经元细胞系，其中其蛋白水解部分的活性，20 S 蛋白酶体，是妥协的一个活性位点的突变，其 催化亚基拟议中的研究将深入了解一个糟糕的 了解神经变性的方面，更具体地确定新的 用于预防泛素化蛋白积聚的治疗靶标 应激神经细胞中的蛋白质。