Structures of α-synuclein filaments from multiple system atrophy

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 () and Michel Goedert ()
Additional contact information
Manuel Schweighauser: MRC Laboratory of Molecular Biology
Yang Shi: MRC Laboratory of Molecular Biology
Airi Tarutani: Tokyo Metropolitan Institute of Medical Science
Fuyuki Kametani: Tokyo Metropolitan Institute of Medical Science
Alexey G. Murzin: MRC Laboratory of Molecular Biology
Bernardino Ghetti: Indiana University School of Medicine
Tomoyasu Matsubara: Tokyo Metropolitan Institute of Gerontology
Taisuke Tomita: The University of Tokyo
Takashi Ando: Nagoya University Graduate School of Medicine
Kazuko Hasegawa: Sagamihara National Hospital
Shigeo Murayama: Tokyo Metropolitan Institute of Gerontology
Mari Yoshida: Aichi Medical University
Masato Hasegawa: Tokyo Metropolitan Institute of Medical Science
Sjors H. W. Scheres: MRC Laboratory of Molecular Biology
Michel Goedert: MRC Laboratory of Molecular Biology

Nature, 2020, vol. 585, issue 7825, 464-469

Abstract: 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 assemblies4–9, 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.

Date: 2020
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-020-2317-6 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:585:y:2020:i:7825:d:10.1038_s41586-020-2317-6

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-020-2317-6

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().