慢性创伤性脑病中的新型 tau 丝折叠包裹疏水分子。

Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules.

机构信息

MRC Laboratory of Molecular Biology, Cambridge, UK.

Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.

出版信息

Nature. 2019 Apr;568(7752):420-423. doi: 10.1038/s41586-019-1026-5. Epub 2019 Mar 20.

DOI:10.1038/s41586-019-1026-5

PMID:30894745

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6472968/

Abstract

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that is associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and dementia pugilistica in retired boxers, CTE has since been identified in former participants of other contact sports, ex-military personnel and after physical abuse. No disease-modifying therapies currently exist, and diagnosis requires an autopsy. CTE is defined by an abundance of hyperphosphorylated tau protein in neurons, astrocytes and cell processes around blood vessels. This, together with the accumulation of tau inclusions in cortical layers II and III, distinguishes CTE from Alzheimer's disease and other tauopathies. However, the morphologies of tau filaments in CTE and the mechanisms by which brain trauma can lead to their formation are unknown. Here we determine the structures of tau filaments from the brains of three individuals with CTE at resolutions down to 2.3 Å, using cryo-electron microscopy. We show that filament structures are identical in the three cases but are distinct from those of Alzheimer's and Pick's diseases, and from those formed in vitro. Similar to Alzheimer's disease, all six brain tau isoforms assemble into filaments in CTE, and residues K274-R379 of three-repeat tau and S305-R379 of four-repeat tau form the ordered core of two identical C-shaped protofilaments. However, a different conformation of the β-helix region creates a hydrophobic cavity that is absent in tau filaments from the brains of patients with Alzheimer's disease. This cavity encloses an additional density that is not connected to tau, which suggests that the incorporation of cofactors may have a role in tau aggregation in CTE. Moreover, filaments in CTE have distinct protofilament interfaces to those of Alzheimer's disease. Our structures provide a unifying neuropathological criterion for CTE, and support the hypothesis that the formation and propagation of distinct conformers of assembled tau underlie different neurodegenerative diseases.

摘要

慢性创伤性脑病（CTE）是一种与反复头部撞击或爆震波暴露相关的神经退行性tau 病。该病最初被描述为拳击手的“击醉综合征”和“拳击痴呆”，此后在其他接触性运动的前参与者、退役军人和遭受身体虐待后也被发现。目前尚无疾病修饰疗法，诊断需要进行尸检。CTE 的特征是神经元、星形胶质细胞和血管周围细胞过程中存在大量过度磷酸化的 tau 蛋白。这与皮质层 II 和 III 中 tau 包含物的积累一起，将 CTE 与阿尔茨海默病和其他 tau 病区分开来。然而，CTE 中 tau 丝的形态以及脑外伤如何导致其形成的机制尚不清楚。在这里，我们使用冷冻电子显微镜将分辨率降低至 2.3Å，从三名 CTE 患者的大脑中确定 tau 丝的结构。我们表明，三种情况下的细丝结构是相同的，但与阿尔茨海默病和皮克病以及体外形成的结构不同。与阿尔茨海默病一样，所有六种脑 tau 同工型在 CTE 中组装成细丝，三重复 tau 的 K274-R379 和四重复 tau 的 S305-R379 形成两个相同 C 形原丝的有序核心。然而，β-螺旋区的不同构象会产生一个在阿尔茨海默病患者大脑中的 tau 丝中不存在的疏水性腔。该腔封闭了与 tau 不相连的额外密度，这表明辅助因子的掺入可能在 CTE 中的 tau 聚集中起作用。此外，CTE 中的细丝具有与阿尔茨海默病不同的原丝界面。我们的结构为 CTE 提供了一个统一的神经病理学标准，并支持以下假设，即组装 tau 的不同构象的形成和传播是不同神经退行性疾病的基础。