Yeast Model--Function/Pathobiology of alpha-Synucuclein

酵母模型--α-突触核蛋白的功能/病理学

• 批准号: 6842092
• 负责人: Susan L. Lindquist
• 金额: $ 22万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6842092
• 关键词: Parkinson' s disease; Saccharomyces cerevisiae; alpha synuclein; biological models; cell biology; conformation; cytotoxicity; fungal genetics; gene expression; genetic library; genetic regulation; genetic screening; genetic techniques; high throughput technology; lipid metabolism; microarray technology; microorganism culture; molecular pathology; oxidative stress; protein degradation; protein folding; protein localization; protein protein interaction; protein structure function

Changes in protein conformation and assembly underlie most processes in cell biology; correspondingly, defects in conformation and assembly are responsible for many human illnesses, including neurodegenerative diseases. Among the most common of these diseases is Parkinson's disease (PD) with a prevalence of approximately 2% after age 65. One of the hallmarks of PD is the presence of cytoplasmic inclusions in neuronal cells, which mainly contain the protein alpha-synuclein (aSyn). The presence of these inclusions of misfolded aSyn is associated with cell death, but the mechanism for toxicity and indeed the function of aSyn remain elusive. We have developed a system to investigate the biological function of aSyn and the toxicity related to its misfolding in the yeast (Saccharomyces cerevisiae). The behavior of aSyn in yeast cells correlates remarkably well with its behavior in mammalian cells. Our goal is to take advantage of the many genetic and molecular techniques available in yeast to investigate the normal and toxic functions of aSyn. We will 1) investigate the cellular quality-control mechanisms influencing aSyn toxicity, 2) identify other modifiers of aSyn toxicity by high throughput screening and 3) determine how factors that modify aSyn toxicity affect a panel of cell biological and biochemical assays we have developed to enhance our understanding of normal and abnormal sSyn biology. Throughout these studies we will collaborate closely with our colleagues at the MGH/MIT Morris Udall Center of Excellence in PD Research to ensure that our results are rapidly assessed in mammalian systems, and reciprocally that the power of yeast genetic and cell biological assays can be employed to facilitate our understanding of any candidate proteins found in the mammalian systems. Our ultimate aim is the development of new strategies for the prevention and treatment of Parkinson's disease.

蛋白质构象和组装的变化是细胞生物学大多数过程的基础；相应地，构象和组装缺陷是导致许多人类疾病的原因，包括神经退行性疾病。其中最常见的是帕金森病 (PD)，65 岁以后患病率约为 2%。PD 的标志之一是神经元细胞中存在细胞质内含物，其中主要含有蛋白质 α-突触核蛋白 (aSyn)。这些错误折叠的 aSyn 内含物的存在与细胞死亡有关，但其毒性机制以及 aSyn 的功能确实存在相关性。 仍然难以捉摸。我们开发了一个系统来研究 aSyn 的生物学功能以及与其在酵母（酿酒酵母）中错误折叠相关的毒性。 aSyn 在酵母细胞中的行为与其在哺乳动物细胞中的行为密切相关。我们的目标是利用酵母中可用的许多遗传和分子技术来研究 aSyn 的正常功能和毒性功能。我们将 1) 研究影响 aSyn 毒性的细胞质量控制机制，2) 通过高通量筛选确定 aSyn 毒性的其他修饰剂，3) 确定修饰 aSyn 毒性的因素如何影响我们开发的一系列细胞生物学和生化检测方法，以增强我们对正常和异常 sSyn 生物学的理解。在整个这些研究过程中，我们将密切合作 与麻省总医院/麻省理工学院 Morris Udall 帕金森病研究卓越中心的同事合作，确保我们的结果在哺乳动物系统中得到快速评估，反过来，酵母遗传和细胞生物学检测的力量也可用于促进我们对哺乳动物系统中发现的任何候选蛋白质的理解。我们的最终目标是开发预防和治疗帕金森病的新策略。