Structure of Protein Aggregates by Solid State NMR

描述(申请人提供)：这项研究的长期目标是对与人类疾病相关的蛋白质聚集和纤颤发展详细的、原子分辨率的结构和功能理解，主要是通过对α-突触核蛋白的研究。与早发性帕金森病(PD)相关的野生型α-突触核蛋白及其突变体(A30P、E46K和A53T)将在几种结构状态下进行检测，包括原纤维、纤维和膜相关复合体。我们认为，这些结构的化学细节决定了α-突触核蛋白的自然生理功能，并且在突变体中和/或在环境应激下，有助于帕金森病的病理。此外，我们认为几种结构状态之间的转换是突触核蛋白的一个基本特征；这种结构可塑性可能是神经元发育和维持所必需的。为了研究这些结构，将使用魔角旋转(MAS)固态核磁共振(SS核磁共振)实验，阐明其他实验技术无法获得的构象和动力学细节。 与公共卫生相关：α-突触核蛋白是帕金森氏症的核心因素。α-突触核蛋白结构和这种疾病之间的确切关系还不是很清楚。我们建议的研究旨在推进这一基础知识，这将有助于更广泛的研究社区开发改进的诊断工具和帕金森氏病的治疗方法。

DESCRIPTION (provided by applicant): The long-term objective of this research is to develop a detailed, atomic-resolution structural and functional understanding of protein aggregation and fibrillation relevant to human disease, principally with studies of alpha-synuclein. Wild type alpha-synuclein and its mutants (A30P, E46K and A53T) associated with early- onset Parkinson's disease (PD) will be examined in several structural states, including protofibrils, fibrils and membrane-associated complexes. We propose that the chemical details of these structures determine the natural physiological function of alpha-synuclein and, in the mutants and/or under environmental stress, contribute to PD pathology. Moreover, we propose that conversion among several structural states is an essential feature of synucleins; this structural plasticity is likely to be required for neuronal development and maintenance. To examine these structures, magic-angle spinning (MAS) solid-state NMR (SSNMR) experiments will be employed, elucidating details of conformation and dynamics that are inaccessible to other experimental techniques. PUBLIC HEALTH RELEVANCE: Alpha-synuclein is a central player in Parkinson's disease. The precise relationships between alpha-synuclein structure and this disease are not yet well understood. Our proposed studies aim to advance this fundamental knowledge, which will assist the broader research community in developing improved diagnostic tools and therapies for Parkinson's disease.