PDF(Pubmed)
Abstract：
The aggregation of proteins into amyloid-like fibrils is seen in many neurodegenerative diseases. Recent years have seen much progress in our understanding of these misfolded protein inclusions, thanks to advances in techniques such as solid-state nuclear magnetic resonance (ssNMR) spectroscopy and cryogenic electron microscopy (cryo-EM). However, multiple repeat-expansion-related disorders have presented special challenges to structural elucidation. This review discusses the special role of ssNMR analysis in the study of protein aggregates associated with CAG repeat expansion disorders. In these diseases, the misfolding and aggregation affect mutant proteins with expanded polyglutamine segments. The most common disorder, Huntington\'s disease (HD), is connected to the mutation of the huntingtin protein. Since the discovery of the genetic causes for HD in the 1990s, steady progress in our understanding of the role of protein aggregation has depended on the integrative and interdisciplinary use of multiple types of structural techniques. The heterogeneous and dynamic features of polyQ protein fibrils, and in particular those formed by huntingtin N-terminal fragments, have made these aggregates into challenging targets for structural analysis. ssNMR has offered unique insights into many aspects of these amyloid-like aggregates. These include the atomic-level structure of the polyglutamine core, but also measurements of dynamics and solvent accessibility of the non-core flanking domains of these fibrils\' fuzzy coats. The obtained structural insights shed new light on pathogenic mechanisms behind this and other protein misfolding diseases.
摘要：
在许多神经退行性疾病中都可以看到蛋白质聚集成淀粉样蛋白样纤维。近年来，我们对这些错误折叠的蛋白质内含物的理解取得了很大进展，由于固态核磁共振（ssNMR）光谱和低温电子显微镜（cryo-EM）等技术的进步。然而,多重重复扩增相关疾病对结构阐明提出了特殊挑战.这篇综述讨论了ssNMR分析在与CAG重复扩增障碍相关的蛋白质聚集体研究中的特殊作用。在这些疾病中,错误折叠和聚集影响具有扩展的聚谷氨酰胺片段的突变蛋白。最常见的疾病，亨廷顿病（HD），与亨廷顿蛋白的突变有关。自从1990年代发现HD的遗传原因以来，我们对蛋白质聚集作用的理解的稳步进展取决于多种类型结构技术的综合和跨学科使用。polyQ蛋白原纤维的异质性和动力学特征，特别是由亨廷顿蛋白N末端片段形成的那些，使这些聚集体成为结构分析的挑战性目标。ssNMR为这些淀粉样蛋白样聚集体的许多方面提供了独特的见解。这些包括聚谷氨酰胺核心的原子级结构，还测量了这些纤维模糊涂层的非核心侧翼结构域的动力学和溶剂可及性。获得的结构见解为这种和其他蛋白质错误折叠疾病背后的致病机制提供了新的思路。
