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致病性α-突触核蛋白细丝结构获解析
2020-05-28 18:06

英国MRC分子生物学实验室Michel Goedert和Sjors H. W. Scheres研究小组,合作解析了引发多系统萎缩症的α-突触核蛋白细丝结构。该项研究成果在线发表在2020年5月27日的《自然》上。

使用冷冻电镜,研究人员发现来自神经系统萎缩症(MSA)患者大脑中α-突触核蛋白内含物是由两种类型的细丝组成,每种细丝都由两个不同的原丝组成。在每种类型的细丝中,两个原丝的界面处都存在非蛋白质分子。使用二维类平均,研究人员发现MSA患者大脑中α-突触核蛋白丝与路易体痴呆症(DLB)患者大脑中的不同,这表明不同的构象体或菌株表达了特定的突触核蛋白。

与tau组件一样,从MSA患者大脑中提取的α-突触核蛋白细丝结构与在体外重组蛋白形成的细丝结构不同,这对于理解人脑这些蛋白的聚集和神经退行的机理具有重要意义。这些发现具有诊断和潜在的治疗意义,尤其是对那些未能在临床上可利用脑成像来鉴定丝状α-突触核蛋白包裹体的患者来说。

研究人员表示,MSA、帕金森氏病、帕金森氏痴呆症和DLB等共核蛋白病是常见的人类神经退行性疾病。现有治疗方法最多只能对症治疗。这些疾病的特征是在脑细胞中存在α-突触核蛋白丝状包裹体,并且这些疾病被认为是由其引起的。然而,尚不清楚人脑中α-突触核蛋白细丝的结构。

附:英文原文

Title: Structures of α-synuclein filaments from multiple system atrophy

Author: Manuel Schweighauser, Yang Shi, Airi Tarutani, Fuyuki Kametani, Alexey G. Murzin, Bernardino Ghetti, Tomoyasu Matsubara, Taisuke Tomita, Takashi Ando, Kazuko Hasegawa, Shigeo Murayama, Mari Yoshida, Masato Hasegawa, Sjors H. W. Scheres, Michel Goedert

Issue&Volume: 2020-05-27

Abstract: Synucleinopathies, which include multiple system atrophy (MSA), Parkinson’s disease, Parkinson’s disease with dementia and dementia with Lewy bodies (DLB), are human neurodegenerative diseases1. 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 α-synuclein in brain cells2,3. However, the structures of α-synuclein filaments from the human brain are unknown. Here, using cryo-electron microscopy, we show that α-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 α-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 assemblies4,5,6,7,8,9, the structures of α-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 α-synuclein inclusions in the human brain.

DOI: 10.1038/s41586-020-2317-6

Source: https://www.nature.com/articles/s41586-020-2317-6

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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