CHARACTERIZATION OF PRION STRAINS AND INFECTIVITY

描述（由申请人提供）：大多数蛋白质构象障碍具有散发和遗传形式。朊病毒疾病，也被称为传染性海绵状脑病（TSE），是独特的，因为它们也有感染性的起源。TSE感染因子是朊病毒蛋白PrP的自繁殖病理亚型。参与各种其他神经退行性疾病的蛋白质形成类似的自繁殖淀粉样结构，但直到最近才假设这些蛋白质聚集体中的一些具有潜在的感染性。TSE的感染起源依赖于朊病毒蛋白以其易于聚集的构象的传播和繁殖。尽管不同物种的TSE的感染机制和基本病理学是保守的，但跨物种传播可能非常低效。这种朊病毒物种屏障的定义因素尚不清楚，但可能与朊病毒蛋白在不同构象（朊病毒株）中繁殖的能力有关。在这个试点项目中，利用酵母朊病毒模型系统，不依赖于临床疾病的发展，以评估朊病毒的传播性和复制倾向。我们将解决两个重要的问题，这将提高我们对朊病毒株的理解，以及感染性和非感染性淀粉样蛋白之间的差异1）是什么使淀粉样蛋白结构具有感染性或非感染性？2)是什么控制着限制感染和朊病毒传播的“物种屏障”？我们有能力根据我们开发的系统和迄今取得的成果，以独特的方式解决这些问题。该试点项目将使我们能够开始利用我们的系统进行结构工作，并为PrP开发和表征类似的系统。 公共卫生相关性：细胞保持活力和正常功能的能力取决于许多蛋白质的协同努力。蛋白质需要在特定的三维结构中正确折叠以获得完整的功能，并且该折叠过程需要称为分子伴侣的辅助分子。蛋白质无法保持正确的折叠是几种毁灭性人类疾病的原因。我们正在研究蛋白质错误折叠的过程是如何发生的，它是如何传播的，以及如何在细胞中纠正这些问题。

DESCRIPTION (provided by applicant): Most protein conformational disorders have both sporadic and inherited forms. Prion diseases, also known as Transmissible Spongiform Encephalopathies (TSEs), are unique in that they also have infectious origins. The TSE infectious agent is a self-propagating pathological isoform of the prion protein, PrP. Proteins involved in various other neurodegenerative diseases form similar self-propagating amyloid structures, but only recently have some of those protein aggregates been hypothesized to be potentially infectious. The infectious origin of TSEs relies upon transmission and propagation of the prion protein in its aggregation-prone conformation. Although the infectious mechanism and fundamental pathology is conserved in TSEs of different species, cross-species transmission can be very inefficient. The defining factors of this prion species barrier are unknown but are likely related to the capacity of prion proteins to propagate in different conformations (prion strains). In this pilot project make use of a yeast prion model system that does not rely on the development of clinical disease to assess prion transmissibility and the propensity for replication. We will address two important questions that will enhance our understanding of the prion strains and the differences between infectious and non-infectious amyloid 1) What makes an amyloid structure infectious or non-infectious? 2) What controls "species barriers" that limit infection and prion transmissibility? We are in a position to address these questions in a unique manner based on the systems that we have developed and the results we have obtained thus far. This pilot project will allow us to begin to utilize our system for structural work and develop and characterize a similar system for PrP. PUBLIC HEALTH RELEVANCE: The ability of a cell to stay alive and function normally depends on the concerted effort of many proteins. Proteins need to be properly folded in a particular three dimensional structure for full functionality and this folding process requires helper molecules called chaperones. The inability of proteins to maintain proper folding is the cause of several devastating human diseases. We are investigating how the process of protein misfolding occurs, how it propagates, and how these problems can be corrected in the cell.