Molecular mechanisms of prion and amyloid propagation

朊病毒和淀粉样蛋白传播的分子机制

基本信息

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
项目类别：
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

项目摘要

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.

家长奖项目摘要朊病毒病是一组传染性神经退行性疾病，包括克雅氏病人类的格斯特曼-施特劳斯勒-沙因克 (GSS) 病、绵羊痒病、牛海绵状病牛的脑病（“疯牛病”）和鹿的慢性消耗性疾病是最有趣的方面。这些疾病的本质是传染性朊病毒病原体，该病原体被认为是一种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。该项目的总体目标是获得高分辨率的结构洞察。朊病毒传播机制以及朊病毒菌株和传播障碍的现象。最后，我们使用由 C 端截短的朊病毒蛋白 PrP23-144 生成的淀粉样原纤维模型，与 GSS 样疾病的 Y145Stop 表型相关的变体该模型的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（核磁共振）光谱和其他生物物理技术提出了三个相互关联的具体目标。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 结合人类高分辨率结构的 PrP23-144 淀粉样原纤维。我们已经确定了 PrP23-144 淀粉样蛋白，这些数据将用于深入了解淀粉样蛋白的结构基础 PrP 淀粉样蛋白播种特异性，传播障碍的体外替代物在第二个目标中，我们将使用。 PrP23-144 淀粉样蛋白模型也阐明了人们知之甚少的朊病毒菌株转换现象最后，第三个目标是确定 PrP 的高分辨率结构。淀粉样蛋白与 GSS 疾病的不同表型相关，后一种见解至关重要，因为目前还没有关于 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。