Structures of α-synuclein filaments from multiple system atrophy
Structures of α-synuclein filaments from multiple system atrophy
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DOI：
10.1038/s41586-020-2317-6
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发表时间：
2020-09-17
期刊：
影响因子：
64.8
通讯作者：
Goedert, Michel
中科院分区：
文献类型：
--
作者：
Schweighauser, Manuel;Shi, Yang;Goedert, Michel
突触核蛋白病，包括多系统萎缩（MSA）、帕金森病、帕金森病伴痴呆和路易体痴呆（DLB），是人类神经退行性疾病（1）。现有的治疗方法充其量只能对症治疗。这些疾病的特征在于存在，并认为是由脑细胞中α-突触核蛋白的丝状包涵体的形成引起的（，）（2）（3）。然而，来自人脑的α-突触核蛋白丝的结构是未知的。在这里，使用冷冻电子显微镜，我们表明，α-突触核蛋白夹杂物从个人与MSA的大脑是由两种类型的丝，其中每一个由两种不同的原丝。在每种类型的丝中，非蛋白质分子存在于两个原丝的界面处。使用二维类平均，我们表明，α-突触核蛋白丝从个人的大脑MSA与DLB的个人，这表明不同的构象或菌株的特点特定的突触核蛋白病的不同。与tau组装体的情况一样（4-9），从患有MSA的个体的脑中提取的α-突触核蛋白丝的结构不同于使用重组蛋白在体外形成的那些，这对于理解人脑中聚集体繁殖和神经变性的机制具有意义。这些发现具有诊断和潜在的治疗相关性，特别是因为能够对人脑中的丝状α-突触核蛋白内含物进行成像的临床需求尚未得到满足。
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.