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

• DOI: 10.1016/j.celrep.2018.05.074
• Publication Date: 2018-06-19T14:43:13Z
• Authors: Daniel R. Whiten; Dezerae Cox; Mathew H. Horrocks; Christopher G. Ta...; Suman De; Patrick Flagmeier; Laura Tosatto; Janet R. Kumita; Heath Ecroyd; Christopher M. Do...; David Klenerman; Mark R. Wilson
• Keywords: Clusterin; Synucleinopathies; Oligomer; Amyloid (mycology); Proteostasis

The aberrant aggregation of α-synuclein is associated with several human diseases, collectively termed the α-synucleinopathies, which includes Parkinson's disease. progression these diseases is, in part, mediated by extracellular oligomers that may exert effects through mechanisms, including prion-like transfer, direct cytotoxicity, and pro-inflammatory actions. In this study, we show two abundant chaperones, clusterin α2-macroglobulin, directly bind to exposed hydrophobic regions on surface oligomers. Using single-molecule fluorescence techniques, found clusterin, unlike exhibits differential binding be related structural differences between previously described forms αS both chaperones reduces ability permeabilize lipid membranes prevents an oligomer-induced increase ROS production cultured neuronal cells. Taken together, data suggest a neuroprotective role for suppressing toxicity