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

The aberrant aggregation of alpha-synuclein is associated with several human diseases, collectively termed the alpha-synucleinopathies, which includes Parkinson's disease. The progression of these diseases is, in part, mediated by extracellular alpha-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 alpha(2)-macroglobulin, directly bind to exposed hydrophobic regions on the surface of alpha-synuclein oligomers. Using single-molecule fluorescence techniques, we found that clusterin, unlike alpha(2)-macroglobulin, exhibits differential binding to alpha-synuclein oligomers that may be related to structural differences between two previously described forms of alpha S 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 alpha-synuclein oligomers.