Mechanism of Prion Neurotropism

描述(由申请人提供)：根据“纯蛋白质假说”，传染性普鲁恩病毒完全由一种错误折叠的糖蛋白PrPSc组成，这种糖蛋白是由一种化学上无法区分的宿主蛋白PrPC的构象变化形成的。Prion可以存在于多个自我复制的菌株中，具有独特的临床、病理和生化特征。只有蛋白质的假说不容易解释的一个现象是选择性神经趋向性，在这种现象中，PrPSc在不同大脑区域的积累模式由PrP菌株决定。细胞识别和区分不同的Pron菌株的机制(S)仍不清楚。在这一竞争性更新应用中，我们提出了三个具体目标来确定Pron神经趋向性的分子基础。1.验证PrPSc糖基化控制PrPSc嗜神经性的假说。2.验证辅助性多阴离子控制Pron菌株的神经趋向性的假说。3.比较不同菌株的蛋白沉淀物的组成。公共卫生相关性：传染性海绵状脑病(TSE)，也被称为普恩病毒病，是一组进展缓慢且总是致命的中枢神经系统感染，可以传染性、散发性和遗传性的形式发生。TSE的一些例子包括人类的库鲁病和克雅氏病(CJD)，牛的牛海绵状脑病(BSE)，鹿和麋鹿的慢性消耗性疾病(CWD)，水貂的传染性水貂脑病(TME)和绵羊的瘙痒病。TSE的感染源是非常规的蛋白质类物质，被称为普恩病毒。在这一应用中，我们建议研究通过大脑传播普恩病毒的机制。这些研究最终可能会改进诊断和治疗Prion TSE的方法，还可能为阿尔茨海默氏症和帕金森氏症等相关神经退行性疾病的病理生理学提供见解。

DESCRIPTION (provided by applicant): According to the "protein-only hypothesis," infectious prions are composed exclusively of a misfolded glycoprotein, PrPSc, which is formed by conformational change of a chemically indistinguishable host protein, PrPC. Prions can exist in multiple, self- replicating strains, characterized by unique clinical, pathological, and biochemical features. A phenomenon not easily explained by the protein-only hypothesis is selective neurotropism, in which the pattern of PrPSc accumulation in different brain regions is determined by the prion strain. The mechanism(s) by which cells recognize and distinguish between different prion strains remains unknown. In this competitive renewal application, we propose three specific aims to determine the molecular basis of prion neurotropism. 1. Test the hypothesis that PrPSc glycosylation controls the neurotropism of prion strains. 2. Test the hypothesis that accessory polyanions control the neurotropism of prion strains. 3. Compare the composition of prion deposits associated with different strains. PUBLIC HEALTH RELEVANCE: Transmissible Spongiform Encephalopathies (TSEs), also known as prion diseases, are a unique group of slowly progressive and invariably fatal infections of the central nervous system, which can occur in infectious, sporadic, and inherited forms. Some examples of TSEs include kuru and Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in deer and elk, transmissible mink encephalopathy (TME) in mink, and scrapie in sheep. The infectious agents of TSEs are unconventional, proteinaceous entities, which have been termed prions. In this application, we propose to study the mechanisms responsible for prion dissemination through the brain. These studies may eventually lead to improved methods to diagnose and treat prion TSEs, and may also provide insights into the pathophysiology of related neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases.