朊病毒Prion淀粉样纤维的三维结构固体核磁共振研究

Prion Diseases, also called Transmissible Spongiform Encephalopathies（TSEs）, are a group of fatal neurodegenerative disorders and infectious. PrP amyloid fibrils are closely associated with occurrence and development of prion diseases. So far, the structure research of mammal PrP amyloid fibrils are most about the secondary structure, atomic-level three-dimensional structures of these fibrils are still unknown..The amino acid sequences of mouse PrP and rabbit PrP are very similar, and mouse belongs to susceptible species to TSEs, but the susceptibility to TSEs of rabbit has not been definitely concluded. Whether there are differences in the structure and assembly mechanism of mouse and rabbit PrP amyloid fibrils is still unclear. In this project, we choose mouse and rabbit PrP amyloid fibrils which could be flexibly labeled by isotopes as the research targets，and we will elucidate the high-resolution three-dimensional structure and assembly mechanism of mouse and rabbit PrP amyloid fibrils by solid-state NMR respectively. The implement of this project will provide indispensable and comprehensive structure bases for understanding the infectious mechanism of prion diseases.

朊病毒疾病，也称为传染性海绵状脑病（TSEs），是一类致死性神经退行性疾病，且具有感染性。PrP淀粉样纤维与该疾病的发生发展密切相关。目前哺乳动物PrP淀粉样纤维的结构研究都是关于二级结构，原子水平的三维结构还不清楚。.小鼠PrP和兔PrP的氨基酸序列具有很高的相似性，但小鼠容易感染TSEs，而兔对于TSEs是否具有感染性尚无明确定论。小鼠和兔PrP淀粉样纤维的三维结构和聚集机制是否有区别都还不清楚。因此，本项目拟选择小鼠PrP和兔PrP的淀粉样纤维作为研究对象，通过对纤维样品进行灵活的同位素标记，运用固体核磁共振技术分别解析它们的高分辨率三维结构，阐明它们的聚集机制，研究结果将为朊病毒疾病的致病机理研究提供必要的更加全面的结构基础。

本项目通过研究朊蛋白淀粉样纤维的三维结构、组装机制和跨种属传播机制，揭示了mPrP纤维成核中心结构主要为β-折叠，纤维单体间沿纤维轴方向平行内对齐排列。在纤维组装过程中，N-端氨基酸片段（23-88）是影响纤维化速率的重要因素。利用所获得的PrP纤维结构信息和PrP纤维跨种属传播的动力学过程，结合分子动力学模拟，发现165位的空间位阻和167位的侧链氢键是影响跨种属诱导纤维化的主要因素，以此为基础提出了PrP淀粉样纤维跨种属传播的分子机制，并发表相关论文。PrP淀粉样纤维与朊病毒疾病的发生发展密切相关，本项目对其三维结构、组装机制和跨种属传播机制的研究具有重要科学意义，可为朊病毒疾病的致病机理研究提供基础结构信息。