Cryo-EM structures of tau filaments from Alzheimer's disease

被引：1394

作者：

Fitzpatrick, Anthony W. P. ^{[1
]}

Falcon, Benjamin ^{[1
]}

He, Shaoda ^{[1
]}

Murzin, Alexey G. ^{[1
]}

Murshudov, Garib ^{[1
]}

Garringer, Holly J. ^{[2
]}

Crowther, R. Anthony ^{[1
]}

Ghetti, Bernardino ^{[2
]}

Goedert, Michel ^{[1
]}

Scheres, Sjors H. W. ^{[1
]}

机构：

[1] MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England

[2] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA

来源：

NATURE | 2017年 / 547卷 / 7662期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

PAIRED HELICAL FILAMENTS; ATOMIC-RESOLUTION STRUCTURE; AMYLOID FIBRILS; NEUROFIBRILLARY TANGLES; FRONTOTEMPORAL DEMENTIA; RECOMBINANT-TAU; BETA STRUCTURE; FINE-STRUCTURE; PROTEIN-TAU; IN-VITRO;

D O I：

10.1038/nature23002

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4-3.5 angstrom resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprising residues 306-378 of tau protein, which adopt a combined cross-beta/beta-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases.

引用

页码：185 / +

页数：18

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