Yeast Model--Function/Pathobiology of alpha-Synucuclein

蛋白质构象和组装的变化是细胞生物学中大多数过程的基础;相应地，构象和组装的缺陷导致许多人类疾病，包括神经退行性疾病。这些疾病中最常见的是帕金森病（PD），65岁后的患病率约为2%。PD的标志之一是神经元细胞中存在细胞质内含物，其主要含有蛋白质α-突触核蛋白（aSyn）。错误折叠的aSyn的这些内含物的存在与细胞死亡相关，但毒性机制和aSyn的功能实际上与细胞死亡相关。 仍然难以捉摸我们已经开发了一个系统来研究aSyn的生物学功能和与其在酵母（酿酒酵母）中的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非常相关。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）通过高通量筛选鉴定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组细胞生物学和生物化学测定，以增强我们对正常和异常sSyn生物学的理解。在这些研究中，我们将密切合作， 与我们在MGH/MIT Morris Udall卓越PD研究中心的同事合作，以确保我们的结果在哺乳动物系统中得到快速评估，并确保酵母遗传和细胞生物学测定的能力可以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。

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.