Iljina, M., Dear, A.J., Garcia, G.A. et al. (9 more authors) (2018) Quantifying co-oligomer formation by α-synuclein. ACS Nano, 12 (11). pp. 10855-10866. ISSN 1936-0851
Abstract
Small oligomers of the protein α-synuclein (αS) are highly cytotoxic species associated with Parkinson’s disease (PD). In addition, αS can form co-aggregates with its mutational variants and with other proteins such as amyloid-β (Aβ) and tau, which are implicated in Alzheimer’s disease. The processes of self-oligomerization and co-oligomerization of αS are, however, challenging to study quantitatively. Here, we have utilized single-molecule techniques to measure the equilibrium populations of oligomers formed in vitro by mixtures of wild-type αS with its mutational variants and with Aβ40, Aβ42, and a fragment of tau. Using a statistical mechanical model, we find that co-oligomer formation is generally more favorable than self-oligomer formation at equilibrium. Furthermore, self-oligomers more potently disrupt lipid membranes than do co-oligomers. However, this difference is sometimes outweighed by the greater formation propensity of co-oligomers when multiple proteins coexist. Our results suggest that co-oligomer formation may be important in PD and related neurodegenerative diseases.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018 American Chemical Society. ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
Keywords: | single-molecule fluorescence; statistical mechanical modeling; cross-aggregation; mixed oligomers; oligomer toxicity |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 01 May 2020 14:58 |
Last Modified: | 02 May 2020 01:25 |
Status: | Published |
Publisher: | American Chemical Society (ACS) |
Refereed: | Yes |
Identification Number: | 10.1021/acsnano.8b03575 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:160183 |