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Substitution of Met-38 to Ile in γ-synuclein found in two patients with amyotrophic lateral sclerosis induces aggregation into amyloid

Lookup NU author(s): Professor Tiago OuteiroORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2024 National Academy of Sciences. All rights reserved.α-,β-,and γ-Synuclein are intrinsically disordered proteins implicated in physiological processes in the nervous system of vertebrates. α-synuclein (αSyn) is the amyloidogenic protein associated with Parkinson's disease and certain other neurodegenerative disorders. Intensive research has focused on the mechanisms that cause αSyn to form amyloid structures, identifying its NAC region as being necessary and sufficient for amyloid assembly. Recent work has shown that a 7-residue sequence (P1) is necessary for αSyn amyloid formation. Although γ-synuclein (γSyn) is 55% identical in sequence to αSyn and its pathological deposits are also observed in association with neurodegenerative conditions, γSyn is resilient to amyloid formation in vitro. Here, we report a rare single nucleotide polymorphism (SNP) in the SNCG gene encoding γSyn, found in two patients with amyotrophic lateral sclerosis (ALS). The SNP results in the substitution of Met38 with Ile in the P1 region of the protein. These individuals also had a second, common and nonpathological, SNP in SNCG resulting in the substitution of Glu110 with Val. In vitro studies demonstrate that the Ile38 variant accelerates amyloid fibril assembly. Contrastingly, Val110 retards fibril assembly and mitigates the effect of Ile38. Substitution of residue 38 with Leu had little effect, while Val retards, and Ala increases the rate of amyloid formation. Ile38 γSyn also results in the formation of γSyn-containing inclusions in cells. The results show how a single point substitution can enhance amyloid formation of γSyn and highlight the P1 region in driving amyloid formation in another synuclein family member.


Publication metadata

Author(s): Aubrey LD, Ninkina N, Ulamec SM, Abramycheva NY, Vasili E, Devine OO, Wilkinson M, MacKinnon E, Limorenko G, Walko M, Muwanga S, Amadio L, Peters OM, Illarioshkin SN, Outeiro TF, Ranson NA, Brockwell DJ, Buchman VL, Radford SE

Publication type: Article

Publication status: Published

Journal: Proceedings of the National Academy of Sciences of the United States of America

Year: 2024

Volume: 121

Issue: 2

Online publication date: 03/01/2024

Acceptance date: 17/11/2023

Date deposited: 23/01/2024

ISSN (print): 0027-8424

ISSN (electronic): 1091-6490

Publisher: National Academy of Sciences

URL: https://doi.org/10.1073/pnas.2309700120

DOI: 10.1073/pnas.2309700120

Data Access Statement: The data are available in the University of Leeds Data depository (https://doi.org/10.5518/1315) (104).

PubMed id: 38170745


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Funding

Funder referenceFunder name
Biotechnology and Biological Sciences research council (BB/V003577/1)
BBSRC (BB/T011157/1)
Engineering and Physical Sciences research council (EP/N013573/1)
Royal Society Research Professorship (RSRP/R1/211057)
the Medical Research Council UK (MR/T011149/1)
the University of Leeds
Wellcome (204963)
Wellcome (215062/Z/18/Z)
Wellcome (221524/Z/20/Z)
the Deutsche Forschung gemeinschaft (German Research Foundation) under Germany’s Excellence Strategy—EXC 2067/1-390729940
the Ministry of Science and Higher Education of RF 075-15-2021-1346
Wellcome (094232)

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