UBIQUITINATED PROTEIN DEGRADATION & NEURODEGENERATION

泛素化蛋白质降解

• 批准号: 6132016
• 负责人: MARIA Emilia FIGUEIREDO-PEREIRA
• 金额: $ 22.5万
• 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/6132016
• 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）：包含物包含 泛素化蛋白是许多神经系统疾病的标志，例如 阿尔茨海默病 (AD)、帕金森病 (PD) 和亨廷顿舞蹈病。共价结合 众所周知，泛素与蛋白质的结合可标记蛋白质的降解 泛素/蛋白酶体途径。这种 ATP 依赖性途径在 异常蛋白质的分解，应迅速去除。虽然 泛素化蛋白的积累与 人们对神经退行性疾病知之甚少，最近发现的突变 泛素和泛素/蛋白酶体途径的酶被发现 分别与散发性 AD 和家族性 PD 密切相关。我们建议 泛素-蛋白质聚集必定是由于功能失常或超载造成的 泛素/蛋白酶体途径或蛋白质结构变化 底物停止降解，并且未能消除 泛素化蛋白破坏细胞稳态，导致 退化。因此，识别压力至关重要 危及泛素/蛋白酶体途径功能的条件 并导致神经元细胞中泛素化蛋白的积累。目标 该项目的主要内容是：（i）确定干扰的压力条件 泛素/蛋白酶体途径的正常运作并了解 它们破坏体内平衡​​的生化机制； (ii) 研究遗传 受这些条件影响的监管途径并确定它们如何变化 泛素/蛋白酶体途径以及相关酶的表达 参与病理过程的蛋白质； (iii) 测试治疗效果 抗氧化剂和抑制剂的有效性或其中一些监管 途径，防止泛素化蛋白质的积累和 神经变性。为了更好地理解所扮演的角色 我们将建立一个稳定的神经退行性变中的泛素/蛋白酶体途径 神经元细胞系，其中其蛋白水解部分 20S 的活性 蛋白酶体，因其活性位点之一的突变而受到损害 催化亚基。拟议的研究将深入了解不良的情况 了解神经退行性变的一个方面，并更具体地识别新的 预防泛素化积累的治疗靶点 应激神经元细胞中的蛋白质。