title: Protein/lipid coaggregates are formed during α-synuclein-induced disruption of lipid bilayers.
abstract: Amyloid formation is associated with neurodegenerative diseases such as Parkinson's disease (PD). Significant α-synuclein (αSN) deposition in lipid-rich Lewy bodies is a hallmark of PD. Nonetheless, an unraveling of the connection between neurodegeneration and amyloid fibrils, including the molecular mechanisms behind potential amyloid-mediated toxic effects, is still missing. Interaction between amyloid aggregates and the lipid cell membrane is expected to play a key role in the disease progress. Here, we present experimental data based on hybrid analysis of two-photon-microscopy, solution small-angle X-ray scattering and circular dichroism data. Data show in real time changes in liposome morphology and stability upon protein addition and reveal that membrane disruption mediated by amyloidogenic αSN is associated with dehydration of anionic lipid membranes and stimulation of protein secondary structure. As a result of membrane fragmentation, soluble αSN:-lipid coaggregates are formed, hence, suggesting a novel molecular mechanism behind PD amyloid cytotoxicity.
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen , Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Andreas
authors.initials: A
authors.lastname: van Maarschalkerweerd
authors.forename: Valeria
authors.initials: V
authors.lastname: Vetri
authors.forename: Annette Eva
authors.initials: AE
authors.lastname: Langkilde
authors.forename: Vito
authors.initials: V
authors.lastname: Foderà
authors.forename: Bente
authors.initials: B
authors.lastname: Vestergaard
mesh_terms: D000682:Amyloid / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002942:Circular Dichroism; D016631:Lewy Bodies / Q000378:metabolism; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D012542:Scattering, Radiation; D014965:X-Rays; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000682:Amyloid; D008051:Lipid Bilayers; D011506:Proteins; D051844:alpha-Synuclein