Single-Molecule Characterization of the Interactions between Extracellular Chaperones and Toxic α-Synuclein Oligomers.
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Whiten, D., Cox, D., Horrocks, M., 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 reports, 23 (12), 3492-3500. https://doi.org/10.1016/j.celrep.2018.05.074
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 which may exert effects by a variety of 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 sensitive single-molecule fluorescence techniques we show that clusterin, unlike α2- macroglobulin, exhibits differential binding to α-synuclein oligomers based on structural properties of the oligomer. 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.
Extracellular Space, Molecular Chaperones, Protein Binding, alpha-Synuclein, Protein Multimerization, Hydrophobic and Hydrophilic Interactions
ECH2020 EUROPEAN RESEARCH COUNCIL (ERC) (669237)
Royal Society (RP150066)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (701013)
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
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/