The Pathological G51D Mutation in Alpha-Synuclein Oligomers Confers Distinct Structural Attributes and Cellular Toxicity
Authors
Xu, Catherine
Castellana-Cruz, Marta
Chen, Serene
Du, Zhen
Knowles, Tuomas
Dobson, Christopher
Cremades, Nunilo
Publication Date
2022-02-15Journal Title
Molecules
Publisher
MDPI AG
Volume
27
Issue
4
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Xu, C., Castellana-Cruz, M., Chen, S., Du, Z., Meisl, G., Levin, A., Mannini, B., et al. (2022). The Pathological G51D Mutation in Alpha-Synuclein Oligomers Confers Distinct Structural Attributes and Cellular Toxicity. Molecules, 27 (4) https://doi.org/10.3390/molecules27041293
Abstract
<jats:p>A wide variety of oligomeric structures are formed during the aggregation of proteins associated with neurodegenerative diseases. Such soluble oligomers are believed to be key toxic species in the related disorders; therefore, identification of the structural determinants of toxicity is of upmost importance. Here, we analysed toxic oligomers of α-synuclein and its pathological variants in order to identify structural features that could be related to toxicity and found a novel structural polymorphism within G51D oligomers. These G51D oligomers can adopt a variety of β-sheet-rich structures with differing degrees of α-helical content, and the helical structural content of these oligomers correlates with the level of induced cellular dysfunction in SH-SY5Y cells. This structure–function relationship observed in α-synuclein oligomers thus presents the α-helical structure as another potential structural determinant that may be linked with cellular toxicity in amyloid-related proteins.</jats:p>
Keywords
α-synuclein, toxic oligomers, Parkinson’s disease, familial mutations, α-helical structure
Sponsorship
Wellcome Trust (094425/Z/10/Z)
Medical Research Council (MR/W01632X/1)
Identifiers
External DOI: https://doi.org/10.3390/molecules27041293
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334142
Rights
Licence:
https://creativecommons.org/licenses/by/4.0/
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