Single-Molecule Characterization of the Interactions between Extracellular Chaperones and Toxic α-Synuclein Oligomers

Daniel R. Whiten, Dezerae Cox, Mathew H. Horrocks, Christopher G. Taylor, Suman De, Patrick Flagmeier, Laura Tosatto, Janet R. Kumita, Heath Ecroyd, Christopher M. Dobson, David Klenerman, Mark R. Wilson

Research output: Contribution to journalArticlepeer-review


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 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 which 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.
Original languageEnglish
Pages (from-to)3492-3500
JournalCell Reports
Issue number12
Early online date19 Jun 2018
Publication statusE-pub ahead of print - 19 Jun 2018


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