title: Two different binding modes of α-synuclein to lipid vesicles depending on its aggregation state.
abstract: Aggregation of α-synuclein is involved in the pathogenesis of Parkinson's disease (PD). Studies of in vitro aggregation of α-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 α-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 α-synuclein monomers, which is accompanied with α-helix formation and requires membranes with high curvature, defects in the lipid packing, and/or negatively charged lipids. Additionally, we demonstrate that membrane-bound α-synuclein monomers are protected from aggregation. Finally, we identified compounds that potently dissolved vesicle-bound α-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.
authors.affiliation: Neurologische Klinik, Klinikum Großhadern, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Högen
authors.forename: Johannes
authors.initials: J
authors.lastname: Levin
authors.forename: Felix
authors.initials: F
authors.lastname: Schmidt
authors.forename: Mario
authors.initials: M
authors.lastname: Caruana
authors.forename: Neville
authors.initials: N
authors.lastname: Vassallo
authors.forename: Hans
authors.initials: H
authors.lastname: Kretzschmar
authors.forename: Kai
authors.initials: K
authors.lastname: Bötzel
authors.forename: Frits
authors.initials: F
authors.lastname: Kamp
authors.forename: Armin
authors.initials: A
authors.lastname: Giese
mesh_terms: D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D031541:Fluorescence Resonance Energy Transfer; D010300:Parkinson Disease / Q000378:metabolism; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D013050:Spectrometry, Fluorescence / Q000379:methods*; D053835:Unilamellar Liposomes / Q000737:chemistry / Q000378:metabolism*; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D010743:Phospholipids; D053835:Unilamellar Liposomes; D051844:alpha-Synuclein; D004121:Dimethyl Sulfoxide