Single-Molecule Characterization of the Interactions between Extracellular Chaperones and Toxic α-Synuclein Oligomers.
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Authors
Whiten, Daniel R
Horrocks, Mathew H
Taylor, Christopher G
Tosatto, Laura
Kumita, Janet R
Ecroyd, Heath
Dobson, Christopher M
Wilson, Mark R
Publication Date
2018-06-19Journal Title
Cell Rep
ISSN
2211-1247
Publisher
Elsevier BV
Volume
23
Issue
12
Pages
3492-3500
Language
eng
Type
Article
Physical Medium
Print
Metadata
Show full item recordCitation
Whiten, D. R., Cox, D., Horrocks, M. H., Taylor, C. G., De, S., Flagmeier, P., Tosatto, L., et al. (2018). Single-Molecule Characterization of the Interactions between Extracellular Chaperones and Toxic α-Synuclein Oligomers.. Cell Rep, 23 (12), 3492-3500. https://doi.org/10.1016/j.celrep.2018.05.074
Abstract
The aberrant aggregation of α-synuclein is associated with several human diseases, collectively termed the α-synucleinopathies, which includes Parkinson's disease. The progression of these diseases is, in part, mediated by extracellular α-synuclein oligomers that may exert effects through several mechanisms, including prion-like transfer, direct cytotoxicity, and pro-inflammatory actions. In this study, we show that two abundant extracellular chaperones, clusterin and α2-macroglobulin, directly bind to exposed hydrophobic regions on the surface of α-synuclein oligomers. Using single-molecule fluorescence techniques, we found that clusterin, unlike α2-macroglobulin, exhibits differential binding to α-synuclein oligomers that may be related to structural differences between two previously described forms of αS oligomers. The binding of both chaperones reduces the ability of the oligomers to permeabilize lipid membranes and prevents an oligomer-induced increase in ROS production in cultured neuronal cells. Taken together, these data suggest a neuroprotective role for extracellular chaperones in suppressing the toxicity associated with α-synuclein oligomers.
Keywords
Extracellular Space, Molecular Chaperones, Protein Binding, alpha-Synuclein, Protein Multimerization, Hydrophobic and Hydrophilic Interactions
Sponsorship
ERC (669237).
Funder references
European Research Council (669237)
Royal Society (RP150066)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (701013)
Identifiers
External DOI: https://doi.org/10.1016/j.celrep.2018.05.074
This record's URL: https://www.repository.cam.ac.uk/handle/1810/283311
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