Molecular mechanisms of prion and amyloid propagation

朊病毒和淀粉样蛋白传播的分子机制

• 批准号: 10387124
• 负责人: Christopher P Jaroniec
• 金额: $ 8.38万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10387124
• 关键词: Amino Acid Sequence; Amyloid; Amyloid Fibrils; Amyloid deposition; Animals; Architecture; Award; Biophysics; Bovine Spongiform Encephalopathy; Brain; C-terminal; Cattle; Characteristics; Chronic Wasting Disease; Creutzfeldt-Jakob Syndrome; Data; Deposition; Disease; Endopeptidase K; Exhibits; Gerstmann-Straussler-Scheinker Disease; Human; In Vitro; Inherited; Link; Magic; Mass Spectrum Analysis; Mesocricetus auratus; Methods; Modeling; Molecular; Molecular Structure; Morphology; Mouse Strains; Mus; Mutation; N-terminal; NMR Spectroscopy; Nature; Neuraxis; Neurodegenerative Disorders; Pathogenesis; Pattern; Phenotype; Play; PrP; PrP amyloid; PrPSc Proteins; Prion Diseases; Prions; Proteins; Public Health; Recombinants; Research; Resistance; Resolution; Scrapie; Seeds; Series; Sheep; Specificity; Structural Models; Structure; Testing; Variant; amyloid structure; base; beta pleated sheet; biophysical properties; biophysical techniques; cerebral amyloidosis; cervid; conformer; design; disease phenotype; experimental study; insight; misfolded protein; mouse model; nervous system disorder; particle; pathogen; prion-like; protein aggregation; recombinant PrP; solid state nuclear magnetic resonance

PROJECT SUMMARY FROM PARENT AWARD Prion diseases are a group of transmissible neurodegenerative disorders that include Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker (GSS) disease in humans, scrapie in sheep, bovine spongiform encephalopathy (“mad cow disease”) in cattle and chronic wasting disease in cervids. The most intriguing aspect of these disorders is the nature of the infectious prion pathogen that is believed to be a misfolded protein aggregate with characteristics of an amyloid. However, the structure of these infectious protein particles remains largely unknown. The overall objective of this project is to gain high-resolution structural insight into the mechanism of prion propagation as well as the phenomena of prion strains and transmissibility barriers. To this end, we use a model of amyloid fibrils generated from the C-terminally truncated prion protein PrP23-144, a variant associated with the Y145Stop phenotype of a GSS-like disease. A unique advantage of this model is that it is amenable to detailed structural characterization at atomic level by solid-state nuclear magnetic resonance (NMR) spectroscopy and other biophysical techniques. Three interrelated specific aims are proposed. The first aim is to determine the high-resolution structures for several different strains of mouse and Syrian hamster PrP23-144 amyloid fibrils using solid-state NMR. In combination with the high-resolution structure of human PrP23-144 amyloid already determined by us, these data will be used to gain insight into the structural basis of PrP amyloid seeding specificities, an in vitro surrogate of transmissibility barriers. In the second aim, we will use the PrP23-144 amyloid model to elucidate the poorly understood phenomenon of prion strain switching as well as the mechanism of strain selection. Finally, the third aim seeks to determine high-resolution structures of PrP amyloids associated with distinct phenotypes of GSS disease. The latter insight is of fundamental importance, as no information is at present available regarding the structures of GSS-associated PrP amyloids or the relationship between specific structural features and disease phenotype.

帕萨特奖项目总结 朊病毒病是包括克雅氏病在内的一组可传播的神经退行性疾病 和人类的Gerstmann-Straussler-Scheinker（GSS）病、绵羊的瘙痒病、牛海绵状 牛的脑病（“疯牛病”）和鹿的慢性消耗病。最有趣的方面是 感染性朊病毒病原体被认为是错误折叠的蛋白质 具有淀粉样蛋白特征的聚集体。然而，这些感染性蛋白质颗粒的结构仍然存在， 大部分未知。该项目的总体目标是获得高分辨率的结构洞察力， 朊病毒传播机制以及朊病毒菌株和传播障碍现象。本 最后，我们使用了一个由C-末端截短的朊病毒蛋白PrP 23 -144产生的淀粉样纤维模型， 与GSS样疾病的Y145 Stop表型相关的变异。这种模式的一个独特优势是， 它可以通过固态核磁共振在原子水平上进行详细的结构表征 (NMR)光谱学和其他生物物理技术。提出了三个相互关联的具体目标。第一 目的是确定几种不同品系的小鼠和叙利亚仓鼠的高分辨率结构 使用固态NMR的PrP 23 -144淀粉样蛋白原纤维。结合人体的高分辨率结构 PrP 23 -144淀粉样蛋白已经由我们确定，这些数据将用于深入了解淀粉样蛋白的结构基础。 PrP淀粉样蛋白接种特异性，一种体外可传递障碍的替代物。在第二个目标中，我们将使用 PrP 23 -144淀粉样蛋白模型，以阐明朊病毒菌株转换的知之甚少的现象 作为菌株选择的机制。最后，第三个目标是确定PrP的高分辨率结构 与GSS疾病的不同表型相关的淀粉样蛋白。后一种见解具有根本的重要性， 因为目前没有关于GSS相关PrP淀粉样蛋白或 特定结构特征与疾病表型之间的关系。