Structures of α-synuclein filaments from multiple system atrophy

被引：498

作者：

Schweighauser, Manuel ^{[1
]}

Shi, Yang ^{[1
]}

Tarutani, Airi ^{[2
,3
]}

Kametani, Fuyuki ^{[2
]}

Murzin, Alexey G. ^{[1
]}

Ghetti, Bernardino ^{[4
]}

Matsubara, Tomoyasu ^{[5
]}

Tomita, Taisuke ^{[3
]}

Ando, Takashi ^{[6
]}

Hasegawa, Kazuko ^{[7
]}

Murayama, Shigeo ^{[5
]}

Yoshida, Mari ^{[8
]}

Hasegawa, Masato ^{[2
]}

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

Goedert, Michel ^{[1
]}

机构：

[1] MRC Lab Mol Biol, Cambridge, England

[2] Tokyo Metropolitan Inst Med Sci, Dept Brain & Neurosci, Tokyo, Japan

[3] Univ Tokyo, Grad Sch Pharmaceut Sci, Tokyo, Japan

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

[5] Tokyo Metropolitan Inst Gerontol, Dept Neuropathol, Tokyo, Japan

[6] Nagoya Univ, Dept Neurol, Grad Sch Med, Nagoya, Aichi, Japan

[7] Sagamihara Natl Hosp, Div Neurol, Sagamihara, Kanagawa, Japan

[8] Aichi Med Univ, Inst Med Sci Aging, Nagakute, Aichi, Japan

来源：

NATURE | 2020年 / 585卷 / 7825期

关键词：

GLIAL CYTOPLASMIC INCLUSIONS; PARKINSONS-DISEASE; LEWY BODIES; OLIVOPONTOCEREBELLAR ATROPHY; PATHOGENIC FIBRIL; TAU; AGGREGATION; DEMENTIA; MUTATION; DEGENERATION;

D O I：

10.1038/s41586-020-2317-6

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：

Synucleinopathies, which include multiple system atrophy (MSA), Parkinson's disease, Parkinson's disease with dementia and dementia with Lewy bodies (DLB), are human neurodegenerative diseases(1). Existing treatments are at best symptomatic. These diseases are characterized by the presence of, and believed to be caused by the formation of, filamentous inclusions of alpha-synuclein in brain cells(,)(2)(3). However, the structures of alpha-synuclein filaments from the human brain are unknown. Here, using cryo-electron microscopy, we show that alpha-synuclein inclusions from the brains of individuals with MSA are made of two types of filament, each of which consists of two different protofilaments. In each type of filament, non-proteinaceous molecules are present at the interface of the two protofilaments. Using two-dimensional class averaging, we show that alpha-synuclein filaments from the brains of individuals with MSA differ from those of individuals with DLB, which suggests that distinct conformers or strains characterize specific synucleinopathies. As is the case with tau assemblies(4-9), the structures of alpha-synuclein filaments extracted from the brains of individuals with MSA differ from those formed in vitro using recombinant proteins, which has implications for understanding the mechanisms of aggregate propagation and neurodegeneration in the human brain. These findings have diagnostic and potential therapeutic relevance, especially because of the unmet clinical need to be able to image filamentous alpha-synuclein inclusions in the human brain.

引用

页码：464 / +

页数：18

共 70 条

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