CHARACTERIZATION OF PRION STRAINS AND INFECTIVITY

描述(申请人提供)：大多数蛋白质构象障碍既有散发性的也有遗传性的。Prion病，也被称为传染性海绵状脑病(TSE)，因为它们也有传染性来源，所以是独特的。TSE感染剂是PrP蛋白的一种自我传播的病理亚型。参与各种其他神经退行性疾病的蛋白质形成了类似的自我传播的淀粉样蛋白结构，但直到最近，才有一些蛋白质聚集体被假设为具有潜在的传染性。TSE的感染性起源依赖于其易于聚集的构象中的Prion蛋白的传播和繁殖。虽然感染机制和基本病理在不同物种的TSE中是保守的，但跨物种传播的效率可能非常低。这种蛋白物种屏障的定义因素尚不清楚，但可能与蛋白在不同构象(蛋白株)中的繁殖能力有关。在这个试点项目中，利用一种不依赖于临床疾病发展的酵母蛋白模型系统来评估蛋白的遗传性和复制倾向。我们将解决两个重要的问题，它们将加强我们对Prion菌株的理解以及传染性和非传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传染性？2)是什么控制了限制感染和Prion传播性的“物种屏障”？我们能够根据我们开发的系统和迄今取得的成果，以独特的方式处理这些问题。这一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。

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.