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

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 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.