tau 蛋白的有序组装与神经退行性变。

Ordered Assembly of Tau Protein and Neurodegeneration.

机构信息

MRC Laboratory of Molecular Biology, Cambridge, UK.

Clifford Allbutt Building, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

出版信息

Adv Exp Med Biol. 2019;1184:3-21. doi: 10.1007/978-981-32-9358-8_1.

DOI:10.1007/978-981-32-9358-8_1

PMID:32096024

Abstract

Tau filaments with distinct morphologies and/or isoform compositions underlie a large number of human neurodegenerative diseases. Their formation is important, because dominantly inherited mutations in MAPT, the tau gene, cause frontotemporal dementia with abundant filamentous tau inclusions. Assembly of tau may begin in a specific region of the brain, from where it spreads to other areas. It remains to be seen if the molecular species underlying tau aggregate-mediated neurodegeneration and propagation are the same or different. In the brains of mice transgenic for human mutant P301S tau, small tau filaments are the predominant seed-competent species. It has been suggested that different conformers of assembled tau may give rise to different human tauopathies, but until recently, it was not possible to study this directly. Electron cryo-microscopy can now be used to determine high-resolution structures of amyloid filaments from human brain. Paired helical and straight tau filaments of Alzheimer's disease are ultrastructural polymorphs. Each filament core is composed of two identical protofilaments extending from G273/304-E380 (in the numbering of the 441 amino acid isoform of human tau), which adopt a combined cross-β/β-helix structure. They comprise the ends of the first or second microtubule-binding repeat (R1 or R2), the whole of R3 and R4, as well as 12 amino acids after R4. By contrast, the core of the narrow filament of Pick's disease consists of a single protofilament extending from K254-F378 of 3R tau, which adopts a cross-β structure. It comprises the last 21 amino acids of R1, all of R3 and R4, as well as 10 amino acids after R4. Wide tau filaments of Pick's disease, which are in the minority, consist of two narrow filaments packed against each other. The tau filament folds of Alzheimer's and Pick's diseases appear to be conserved between different cases of disease. These findings show that filamentous tau adopts one fold in Alzheimer's disease and a different fold in Pick's disease, establishing the existence of distinct conformers.

摘要

大量的人类神经退行性疾病都以下述具有独特形态和/或同工型组成的 tau 丝为基础。tau 丝的形成很重要，因为 MAPT（tau 基因）中的显性遗传突变会导致富含丝状 tau 的包涵体的额颞叶痴呆。tau 的组装可能首先在大脑的特定区域开始，然后从那里扩散到其他区域。tau 聚集介导的神经退行性变和传播的分子物种是否相同或不同，还有待观察。在携带人类突变 P301S tau 的转基因小鼠大脑中，小 tau 丝是主要的种属竞争物种。有人认为，组装 tau 的不同构象可能导致不同的人类 tau 病，但直到最近，才有可能直接对此进行研究。电子冷冻显微镜现在可用于确定来自人脑的淀粉样纤维的高分辨率结构。阿尔茨海默病的成对螺旋直 tau 丝是超微结构多态性。每个纤维核心由两条从 G273/304-E380（人类 tau 的 441 个氨基酸同工型的编号）延伸的相同原丝组成，这些原丝采用组合的交叉-β/β-螺旋结构。它们构成第一个或第二个微管结合重复（R1 或 R2）的末端、整个 R3 和 R4 以及 R4 之后的 12 个氨基酸。相比之下，Pick 病的窄纤维核心由从 3R tau 的 K254-F378 延伸的单个原丝组成，该原丝采用交叉-β结构。它包括 R1 的最后 21 个氨基酸、R3 和 R4 的全部以及 R4 之后的 10 个氨基酸。Pick 病的少数宽 tau 丝由相互对接的两条窄丝组成。阿尔茨海默病和 Pick 病的 tau 纤维折叠在不同的疾病病例之间似乎是保守的。这些发现表明，丝状 tau 在阿尔茨海默病中采用一种折叠，在 Pick 病中采用另一种折叠，从而确立了不同构象的存在。