New SNCA mutation and structures of α-synuclein filaments from juvenile-onset synucleinopathy

DOI: 10.1007/s00401-023-02550-8

Authors: Yang Yang (Medical Research Council Laboratory of Molecular Biology) , Holly J. Garringer (Indiana University School of Medicine) , Yang Shi (MRC Laboratory of Molecular Biology) , Sofia Lovestam (Medical Research Council Laboratory of Molecular Biology) , Sew Peak-Chew (Medical Research Council Laboratory of Molecular Biology) , Xianjun Zhang (Thermo Fisher Scientific) , Abhay Kotecha (Thermo Fisher Scientific) , Mehtap Bacioglu (University of Cambridge) , Atsuo Koto (Yomiuri-Land Keiyu Hospital) , Masaki Takao (National Center of Neurology and Psychiatry (Japan)) , Maria Grazia Spillantini (University of Cambridge) , Bernardino Ghetti (Indiana University School of Medicine) , Ruben Vidal (Indiana University School of Medicine) , Alexey G. Murzin (Medical Research Council Laboratory of Molecular Biology) , Sjors H. W. Scheres (MRC Laboratory of Molecular Biology) , Michel Goedert (Medical Research Council Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acta Neuropathologica , VOL 26

State: Published (Approved)
Published: February 2023
Diamond Proposal Number(s): 23268

Abstract: A 21-nucleotide duplication in one allele of SNCA was identified in a previously described disease with abundant α-synuclein inclusions that we now call juvenile-onset synucleinopathy (JOS). This mutation translates into the insertion of MAAAEKT after residue 22 of α-synuclein, resulting in a protein of 147 amino acids. Both wild-type and mutant proteins were present in sarkosyl-insoluble material that was extracted from frontal cortex of the individual with JOS and examined by electron cryo-microscopy. The structures of JOS filaments, comprising either a single protofilament, or a pair of protofilaments, revealed a new α-synuclein fold that differs from the folds of Lewy body diseases and multiple system atrophy (MSA). The JOS fold consists of a compact core, the sequence of which (residues 36–100 of wild-type α-synuclein) is unaffected by the mutation, and two disconnected density islands (A and B) of mixed sequences. There is a non-proteinaceous cofactor bound between the core and island A. The JOS fold resembles the common substructure of MSA Type I and Type II dimeric filaments, with its core segment approximating the C-terminal body of MSA protofilaments B and its islands mimicking the N-terminal arm of MSA protofilaments A. The partial similarity of JOS and MSA folds extends to the locations of their cofactor-binding sites. In vitro assembly of recombinant wild-type α-synuclein, its insertion mutant and their mixture yielded structures that were distinct from those of JOS filaments. Our findings provide insight into a possible mechanism of JOS fibrillation in which mutant α-synuclein of 147 amino acids forms a nucleus with the JOS fold, around which wild-type and mutant proteins assemble during elongation.

Journal Keywords: α-Synuclein; Duplication mutation in SNCA; Juvenile-onset synucleinopathyl; Parkinson's disease; Multiple system atrophy; Cryo-electron microscopy

Diamond Keywords: Parkinson's Disease

Subject Areas: Biology and Bio-materials

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios IV-Titan Krios IV at Diamond

Added On: 03/03/2023 08:33

Documents:
s00401-023-02550-8.pdf

Discipline Tags:

Neurodegenerative Diseases Non-Communicable Diseases Health & Wellbeing Genetics Neurology Structural biology Life Sciences & Biotech

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)