Replication mechanism of human prions

摘要 朊病毒是一种独特的，仅蛋白质的感染因子，是导致一组致命的神经退行性疾病的原因 例如人类的克雅氏病，牛的牛海绵状脑病， 鹿和麋鹿的慢性消耗性疾病。人类朊病毒疾病尤其知之甚少，主要是由于 其巨大的表型异质性来自于大范围的不同人类朊病毒株。是 普遍认为朊病毒通过与正常朊病毒蛋白（PrPC）结合并将其转化而增殖 转化为构象不同的致病分子（PrPSc），但这一过程的机制仍然存在 不清楚越来越多的研究表明，小的，相对较小的， 蛋白酶敏感的寡聚体似乎控制疾病发病机制中的两个基本步骤：朊病毒 复制率和毒性。拟议研究的主要目标之一是推进分子生物学， 对低聚PrPSc（oPrPSc）的性质以及这些性质的机制的水平理解 寡聚体在散发性Creutzfeldt-Jakob病不同表型的致病过程中的作用 （sCJD）。第一个具体目标是描述oPrPSc的结构组织特征，并定义其作用 组织的复制，繁殖和毒性的最常见的菌株的sCJD。第二个目的 是确定PrPC和oPrPSc之间相互作用的早期关键构象步骤， 在触发毒性信号、制造人类朊病毒和控制朊病毒进化方面发挥重要作用。如果 成功的，拟议的研究不仅应该揭示人类朊病毒的致病机制， 疾病，而且还提供了理解PrPSc结构和应变之间的关系的基础 人类朊病毒的特性

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.