Two different binding modes of ?-synuclein to lipid vesicles depending on its aggregation state.

ABSTRACT: Aggregation of ?-synuclein is involved in the pathogenesis of Parkinson's disease (PD). Studies of in vitro aggregation of ?-synuclein are rendered complex because of the formation of a heterogeneous population of oligomers. With the use of confocal single-molecule fluorescence techniques, we demonstrate that small aggregates (oligomers) of ?-synuclein formed from unbound monomeric species in the presence of organic solvent (DMSO) and iron (Fe(3+)) ions have a high affinity to bind to model membranes, regardless of the lipid-composition or membrane curvature. This binding mode contrasts with the well-established membrane binding of ?-synuclein monomers, which is accompanied with ?-helix formation and requires membranes with high curvature, defects in the lipid packing, and/or negatively charged lipids. Additionally, we demonstrate that membrane-bound ?-synuclein monomers are protected from aggregation. Finally, we identified compounds that potently dissolved vesicle-bound ?-synuclein oligomers into monomers, leaving the lipid vesicles intact. As it is commonly believed that formation of oligomers is related PD progression, such compounds may provide a promising strategy for the design of novel therapeutic drugs in Parkinson's disease.

SUBMITTER: Hogen T 

PROVIDER: S-EPMC3318129 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature