Mechanism of Prion Neurotropism

描述（由申请人提供）：根据“蛋白质唯一假说”，感染性朊病毒完全由错误折叠的糖蛋白PrPSc组成，该糖蛋白是由化学上难以区分的宿主蛋白PrPC的构象变化形成的。朊病毒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。选择性嗜神经性是一种不容易用蛋白质假说解释的现象，在这种现象中，PrPSc在不同脑区积累的模式是由朊病毒株决定的。细胞识别和区分不同朊病毒株的机制尚不清楚。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朊病毒嗜神经性的分子基础。1. 验证PrPSc糖基化控制朊病毒株嗜神经性的假设。2. 验证副多阴离子控制朊病毒株嗜神经性的假设。3. 比较不同菌株的朊病毒沉积物组成。公共卫生相关性：传染性海绵状脑病（tse），也称为朊病毒疾病，是一组独特的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）和羊的痒病。tse的传染因子是非常规的蛋白质实体，被称为朊病毒。在这个应用中，我们建议研究朊病毒通过大脑传播的机制。这些研究可能最终导致改进朊病毒tse的诊断和治疗方法，也可能为相关神经退行性疾病（如阿尔茨海默病和帕金森病）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.