CHARACTERIZATION OF PRION STRAINS AND INFECTIVITY

描述（由申请人提供）：大多数蛋白质构象障碍有散发性和遗传性两种形式。朊病毒疾病，也被称为传染性海绵状脑病（tse），其独特之处在于它们也具有传染性起源。TSE传染因子是朊蛋白PrP的一种自我繁殖的病理亚型。参与各种其他神经退行性疾病的蛋白质形成类似的自我繁殖的淀粉样蛋白结构，但直到最近才有人假设其中一些蛋白质聚集体具有潜在的传染性。传染性起源的tse依赖于传播和繁殖的朊病毒蛋白在其易于聚集的构象。虽然不同物种的传染机制和基本病理是保守的，但跨物种传播可能非常低效。这种朊病毒物种屏障的决定性因素尚不清楚，但可能与朊病毒蛋白以不同构象（朊病毒株）繁殖的能力有关。在这个试点项目中，利用一个不依赖于临床疾病发展的酵母朊病毒模型系统来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，这两个问题将增强我们对朊病毒菌株以及传染性和非传染性淀粉样蛋白之间差异的理解1)是什么使淀粉样蛋白结构具有传染性或非传染性？2)是什么控制了限制感染和朊病毒传播的“物种屏障”？我们能够根据我们所发展的制度和迄今取得的成果，以一种独特的方式解决这些问题。这个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开发和描述类似的系统。

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.