Replication mechanism of human prions

摘要 Prion是一种独特的、仅含蛋白质的感染性病原体，可导致一组致命的神经退行性变 人类的克雅氏病、牛的牛海绵状脑病和 鹿和麋鹿的慢性消耗性疾病。人类的普恩病毒疾病尤其鲜为人知，这主要是由于 到它们巨大的表型异质性，这种表型异质性来自于人类不同的Pron菌株的大范围。它是 普遍认为，普里恩试剂通过与正常普鲁恩蛋白(PrPC)结合并将其转化而增殖 形成一种构象不同的致病分子(PrPSc)，但这一过程的机制仍然 不清楚。越来越多的研究表明，在细小的、相对较小的普恩病毒病的发病机制中起关键作用 似乎控制疾病发病机制的两个基本步骤的蛋白酶敏感寡聚体：Pron 复制率和毒性。拟议研究的主要目标之一是推动分子 对低聚PrPSc(OPrPSc)的性质及其作用机制有深入的了解 寡聚体在不同表型散发性克雅病发病过程中的作用 (《华尔街日报》)第一个具体目标是描述oPrPSc的结构组织并确定其作用 在最常见的sCJD菌株的复制、繁殖和毒性中的组织。第二个目标 是确定PrPC和oPrPSc之间相互作用的早期关键构象步骤，这些步骤可能 在触发有毒信号、创造人类普恩病毒和控制普恩病毒进化方面发挥重要作用。如果 成功，拟议的研究不仅应该为人类Pron的致病机制提供新的线索 但也为理解PrPSc结构和应变之间的关系提供了基础 人类普里恩的性质。

ABSTRACT Prions are unique, protein-only infectious agents that are responsible for a group of fatal neurodegenerative diseases such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle and chronic wasting disease in deer and elk. Human prion diseases are especially poorly understood, largely due to their vast phenotypic heterogeneity that arises from a large spectrum of diverse human prion strains. It is generally accepted that the prion agent multiplies by binding to normal prion protein (PrPC) and converting it into a conformationally distinct pathogenic molecule (PrPSc), but the mechanism of this process remains unclear. A growing number of studies suggest a critical role in prion disease pathogenesis of small, relatively protease sensitive oligomers that appear to control two fundamental steps in the disease pathogenesis: prion replication rate and toxicity. One of the primary objectives of the proposed research is to advance molecular level understanding of the properties of oligomeric PrPSc (oPrPSc) and the mechanism by which these oligomers contribute to the pathogenic process in different phenotypes of sporadic Creutzfeldt-Jakob disease (sCJD). The first Specific Aim is to characterize the structural organization of oPrPSc and define the role of this organization in the replication, propagation and toxicity of the most common strains of sCJD. The second Aim is to identify early critical conformational steps in the interaction between PrPC and oPrPSc, the steps that likely play a major role in triggering toxic signaling, creating human prions and controlling prion evolution. If successful, the proposed studies should not only shed new light on the pathogenic mechanism in human prion disorders, but also provide a basis for understanding the relationship between PrPSc structure and strain properties of human prions.