皮质基底节变性中存在新型tau蛋白丝折叠
2020-02-14   阅读:274   来源:自然

英国MRC的分子生物学实验室Sjors H. W. Scheres、Michel Goedert等研究人员合作揭示皮质基底节变性(CBD)中的新型tau蛋白丝折叠。2020年2月12日,《自然》在线发表了这项成果。

研究人员使用冷冻电镜(cryo-EM)报道了从三名患有CBD的人大脑中提取的tau丝的结构。它们在病例之间是相同的,但与阿尔茨海默氏病、匹克氏病和慢性创伤性脑病(CTE)不同。CBD丝的核心包含tau的K274-E380残基,跨越R1的最后一个残基,R2、R3和R4的整个残基,以及R4之后的12个氨基酸。其利用新型四层折叠,从而包含了很大的非蛋白质密度。后者被R2的赖氨酸残基290和294和R4之后的序列370的侧链包围。CBD是第一种具有已知结构丝的4R tau疾病。
 
据了解,CBD是一种神经退行性tau疾病,其特征是运动和认知障碍。在CBD病例中,MAPT(tau基因)的H1单倍型的频率高于对照组,并且全基因组关联研究确定了其他危险因素。根据组织学,星形胶质斑块可诊断为CBD,并且通过SDS-PAGE可发现37 kDa的不溶性tau片段。如同进行性核上性麻痹(PSP)、球状神经胶质tau疾病(GGT)和嗜银粒病(AGD)一样,CBD的特征是丰富的丝状tau内含物,其由具有四个微管结合重复序列(4R)的亚型组成。这将4R tau疾病与匹克氏病(其病理丝由三个重复tau亚型构成)以及阿尔茨海默氏病和CTE(其病理丝同时存在3R和4R tau亚型)区分开来。
 
附:英文原文

Title: Novel tau filament fold in corticobasal degeneration

Author: Wenjuan Zhang, Airi Tarutani, Kathy L. Newell, Alexey G. Murzin, Tomoyasu Matsubara, Benjamin Falcon, Ruben Vidal, Holly J. Garringer, Yang Shi, Takeshi Ikeuchi, Shigeo Murayama, Bernardino Ghetti, Masato Hasegawa, Michel Goedert, Sjors H. W. Scheres

Issue&Volume: 2020-02-12

Abstract: Corticobasal degeneration (CBD) is a neurodegenerative tauopathy that is characterised by motor and cognitive disturbances1–3. A higher frequency of the H1 haplotype of MAPT, the tau gene, is present in cases of CBD than in controls4,5 and genome-wide association studies have identified additional risk factors6. By histology, astrocytic plaques are diagnostic of CBD7,8, as are detergent-insoluble tau fragments of 37 kDa by SDS–PAGE9. Like progressive supranuclear palsy (PSP), globular glial tauopathy (GGT) and argyrophilic grain disease (AGD)10, CBD is characterized by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats (4R)11–15. This distinguishes 4R tauopathies from Pick’s disease, filaments of which are made of three-repeat (3R) tau isoforms, and from Alzheimer’s disease and chronic traumatic encephalopathy (CTE), where both 3R and 4R tau isoforms are found in the filaments16. Here we report the structures of tau filaments extracted from the brains of three individuals with CBD using electron cryo-microscopy (cryo-EM). They were identical between cases, but distinct from those of Alzheimer’s disease, Pick’s disease and CTE17–19. The core of CBD filaments comprises residues K274-E380 of tau, spanning the last residue of R1, the whole of R2, R3 and R4, as well as 12 amino acids after R4. It adopts a novel four-layered fold, which encloses a large non-proteinaceous density. The latter is surrounded by the side chains of lysine residues 290 and 294 from R2 and 370 from the sequence after R4. CBD is the first 4R tauopathy with filaments of known structure.

DOI: 10.1038/s41586-020-2043-0

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