MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, United Kingdom.
MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, United Kingdom.
Curr Opin Struct Biol. 2020 Oct;64:17-25. doi: 10.1016/j.sbi.2020.05.011. Epub 2020 Jun 27.
Assembly of microtubule-associated protein tau into filamentous inclusions underlies many human neurodegenerative diseases, called tauopathies. Tau inclusions display distinct cellular and neuroanatomical distributions in different tauopathies. Morphological and biochemical differences suggest that tau filaments adopt disease-specific molecular conformers, similar to prion strains. Breakthroughs in electron cryo-microscopy have recently yielded atomic structures of tau filaments extracted from the brains of individuals with various tauopathies. Each disease is characterised by a unique tau filament fold, which is conserved among individuals with the same disease. In vitro aggregation yields different structures from those observed in brain. Tau isoform composition, post-translational modifications or interactions with cofactors may determine which structures are formed in brain. Understanding filament formation will be central to deciphering the molecular mechanisms that underlie human tauopathies.
微管相关蛋白 tau 的组装成纤维状包含物是许多人类神经退行性疾病的基础，这些疾病被称为 tau 病。tau 包含物在不同的 tau 病中显示出不同的细胞和神经解剖分布。形态和生化差异表明 tau 纤维采用疾病特异性的分子构象，类似于朊病毒株。电子冷冻显微镜的突破最近提供了从各种 tau 病患者大脑中提取的 tau 纤维的原子结构。每种疾病的特征是独特的 tau 纤维折叠，在患有相同疾病的个体中是保守的。体外聚集产生的结构与在大脑中观察到的结构不同。tau 同工型组成、翻译后修饰或与辅助因子的相互作用可能决定了在大脑中形成的结构。了解纤维的形成将是破译导致人类 tau 病的分子机制的核心。
