Novel tau filament fold in corticobasal degeneration
Novel tau filament fold in corticobasal degeneration
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DOI：
10.1038/s41586-020-2043-0
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发表时间：
2020-02-12
期刊：
影响因子：
64.8
通讯作者：
Scheres, Sjors H. W.
中科院分区：
文献类型：
--
作者：
Zhang, Wenjuan;Tarutani, Airi;Scheres, Sjors H. W.
对皮质基底节变性患者的 tau 丝进行冷冻电子显微镜观察，发现了以前未见过的四层折叠，与阿尔茨海默氏病、皮克氏病和慢性创伤性脑病中观察到的丝结构不同。皮质基底节变性 (CBD) 是一种神经退行性 tau 病 - tau 蛋白形成的一类疾病 大脑中的不溶性内含物 - 其特征是运动和认知障碍 (1-3)。 MAPT（tau 基因）的 H1 单倍型在 CBD 病例中出现的频率高于对照组 (4,5)，全基因组关联研究已经确定了其他危险因素 (6)。通过组织学，星形细胞斑块可诊断 CBD7,8；通过 SDS-PAGE 检测，洗涤剂不溶的 tau(9) 37 kDa 片段也是如此。与进行性核上性麻痹、球状神经胶质 tau 病和嗜银颗粒病 (10) 一样，CBD 的特点是含有丰富的丝状 tau 包涵体，这些包涵体由具有四个微管结合重复序列的亚型组成 (11-15)。这将此类“4R”tau蛋白病与皮克氏病（其细丝由三重复 (3R) tau 同工型组成）以及阿尔茨海默氏病和慢性创伤性脑病 (CTE)（其中在细丝中同时发现 3R 和 4R 同工型）区分开来 (16)。在这里，我们使用冷冻电子显微镜分析从三个 CBD 个体大脑中提取的 tau 蛋白丝的结构。这些细丝在不同病例之间是相同的，但与阿尔茨海默病、皮克病和 CTE17-19 中观察到的细丝不同。 CBD 丝的核心包含 tau 残基赖氨酸 274 至谷氨酸 380，跨越 R1 重复序列的最后一个残基、整个 R2、R3 和 R4 重复序列以及 R4 之后的 12 个氨基酸。核心采用了以前从未见过的四层折叠，其中包含了大量的非蛋白质密度。该密度被来自R2的赖氨酸残基290和294以及来自R4之后的序列的赖氨酸370的侧链包围。
Cyro-electron microscopy of tau filaments from people with corticobasal degeneration reveals a previously unseen four-layered fold, distinct from the filament structures seen in Alzheimer's disease, Pick's disease and chronic traumatic encephalopathy.Corticobasal degeneration (CBD) is a neurodegenerative tauopathy-a class of disorders in which the tau protein forms insoluble inclusions in the brain-that is characterized by motor and cognitive disturbances(1-3). The H1 haplotype of MAPT (the tau gene) is present in cases of CBD at a higher frequency than in controls(4,5), and genome-wide association studies have identified additional risk factors(6). By histology, astrocytic plaques are diagnostic of CBD7,8; by SDS-PAGE, so too are detergent-insoluble, 37 kDa fragments of tau(9). Like progressive supranuclear palsy, globular glial tauopathy and argyrophilic grain disease(10), CBD is characterized by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats(11-15). This distinguishes such '4R' tauopathies from Pick's disease (the filaments of which are made of three-repeat (3R) tau isoforms) and from Alzheimer's disease and chronic traumatic encephalopathy (CTE) (in which both 3R and 4R isoforms are found in the filaments)(16). Here we use cryo-electron microscopy to analyse the structures of tau filaments extracted from the brains of three individuals with CBD. These filaments were identical between cases, but distinct from those seen in Alzheimer's disease, Pick's disease and CTE17-19. The core of a CBD filament comprises residues lysine 274 to glutamate 380 of tau, spanning the last residue of the R1 repeat, the whole of the R2, R3 and R4 repeats, and 12 amino acids after R4. The core adopts a previously unseen four-layered fold, which encloses a large nonproteinaceous density. This density is surrounded by the side chains of lysine residues 290 and 294 from R2 and lysine 370 from the sequence after R4.