title: Cholesterol facilitates interactions between α-synuclein oligomers and charge-neutral membranes.
abstract: Oligomeric species formed during α-synuclein fibrillation are suggested to be membrane-disrupting agents, and have been associated with cytotoxicity in Parkinson's disease. The majority of studies, however, have revealed that the effect of α-synuclein oligomers is only noticeable on systems composed of anionic lipids, while the more physiologically relevant zwitterionic lipids remain intact. We present experimental evidence for significant morphological changes in zwitterionic membranes containing cholesterol, induced by α-synuclein oligomers. Depending on the lipid composition, model membranes are either unperturbed, disrupt, or undergo dramatic morphological changes and segregate into structurally different components, which we visualize by 2-photon fluorescence microscopy and generalized polarization analysis using the fluorescent probe Laurdan. Our results highlight the crucial role of cholesterol for mediating interactions between physiologically relevant membranes and α-synuclein.
authors: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors: Andreas
authors: A
authors: van Maarschalkerweerd
authors: Dipartimento di Fisica e Chimica, Universitá di Palermo, Viale delle Scienze Ed. 18, 90128 Palermo, Italy. Electronic address: valeria.vetri@unipa.it.
authors: Valeria
authors: V
authors: Vetri
authors: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark. Electronic address: Bente.Vestergaard@sund.ku.dk.
authors: Bente
authors: B
authors: Vestergaard
mesh_terms: D015081:2-Naphthylamine / Q000031:analogs & derivatives / Q000737:chemistry; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000737:chemistry; D007848:Laurates / Q000737:chemistry; D011485:Protein Binding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D005456:Fluorescent Dyes; D007848:Laurates; D051844:alpha-Synuclein; D002784:Cholesterol; D015081:2-Naphthylamine; C065580:laurdan
keywords: Amyloid; Laurdan fluorescence; Membrane phase separation; Membranes; Multiphoton microscopy; Oligomer; Parkinson’s disease; α-Synuclein