Genetic Study of the Yeast Prion-Interacting Proteins

描述（由申请方提供）：不可治愈的感染性神经退行性疾病 疾病，如“疯牛病”和人类克雅氏病， 推测是由一种异常的聚集倾向蛋白质同种型传播的 （朊病毒）。朊病毒聚集体被认为能够接种聚集体， 正常的细胞蛋白质，转化成朊病毒朊病毒病理学 疾病使人想起其他蛋白质组装障碍（如 老年痴呆症？与淀粉样蛋白聚集相关的疾病。在酵母中朊病毒 控制通过细胞质遗传的表型性状。这提供了一种分子 蛋白质遗传的基础。正如几种不相关的蛋白质所表现出的那样 朊病毒形成的潜力，很可能是基于蛋白质的遗传可能发挥作用， 重要的生物学作用。酵母基因分析的力量使酵母成为 研究朊病毒传播的一般机制的有用模型。虽然许多 蛋白质可以在体外形成淀粉样聚集体，其中只有一些是 能够在体内传递聚集状态。这意味着细胞 通常能够防止聚集传播。然而朊病毒正在克服 细胞防御系统此外，我们的研究证明， 细胞应激防御机制成为朊病毒的重要组成部分 在酵母细胞中繁殖。这项研究的总体目标是揭示细胞系统控制朊病毒形成和传播的机制， 酵母细胞这将解释环境和生理因素 诱导基于蛋白质遗传变异，并可能提供一种新的工具， 通过改变细胞调节系统来治疗聚集性疾病。 蛋白质影响朊病毒的形成和繁殖的酵母将 研究：进化保守的应激相关分子伴侣 Hsp 100和Hsp 70组;泛素系统，通常参与靶向 错误折叠的蛋白质降解;和细胞骨架组装蛋白参与 形成皮层肌动蛋白斑块和内吞囊泡。具体目标 建议如下：1）研究朊病毒的调控机制， 热休克蛋白平衡2)为了研究泛素系统在细胞凋亡中的作用， 酵母朊病毒的细胞控制3)为了研究朊病毒和 酵母中的细胞分裂素相关结构。

DESCRIPTION (provided by applicant): Incurable infectious neurodegenerative diseases, such as "mad cow" disease and human Creutzefeldt-Jacob disease, are postulated to be transmitted by an abnormal aggregation-prone protein isoform (prion). Prion aggregates are believed to be capable of seeding aggregation of the normal cellular protein, converting it into a prion. Pathology of prion diseases is reminiscent of other protein assembly disorders (such as Alzheimer?s disease) associated with amyloid-like aggregation. In yeast, prions control phenotypic traits inherited via cytoplasm. This provides a molecular basis for protein-based inheritance. As several unrelated proteins exhibit prion-forming potential, it is likely that protein-based inheritance may play an important biological role. The power of yeast genetic analysis makes yeast a useful model for studying general mechanisms of prion propagation. While many proteins can form amyloid-like aggregates in vitro, only some of them are capable of transmitting the aggregated state in vivo. This means that cells are normally able to prevent aggregate propagation. However, prions are overcoming the cellular defense systems. Moreover, our research has proven that the cellular stress-defense machinery becomes an essential component of prion propagation in the yeast cell. The overall, goal of this proposal is to uncover mechanisms by which cellular systems control prion formation and propagation in the yeast cell. This will explain how environmental and physiological factors induce protein-based inheritable variations, and may provide a new tool for curing aggregation-based disorders by altering the cellular regulatory systems. Proteins affecting prion formation and propagation in yeast will be investigated: stress-related chaperones of the evolutionary conserved Hsp100 and Hsp70 groups; ubiquitin system, normally involved in targeting misfolded proteins for degradation; and cytoskeletal assembly proteins involved in formation of cortical actin patches and endocytic vesicles. Specific Aims of the proposal are as follows: 1) To study a mechanism of prion regulation by the heat shock protein balance. 2) To study the role of ubiquitin system in the cellular control of yeast prions. 3) To study interactions between prions and cytoskeleton-associated structures in yeast.