title: Direct Correlation Between Ligand-Induced α-Synuclein Oligomers and Amyloid-like Fibril Growth.
abstract: Aggregation of proteins into amyloid deposits is the hallmark of several neurodegenerative diseases such as Alzheimer's and Parkinson's disease. The suggestion that intermediate oligomeric species may be cytotoxic has led to intensified investigations of pre-fibrillar oligomers, which are complicated by their transient nature and low population. Here we investigate alpha-synuclein oligomers, enriched by a 2-pyridone molecule (FN075), and the conversion of oligomers into fibrils. As probed by leakage assays, the FN075 induced oligomers potently disrupt vesicles in vitro, suggesting a potential link to disease related degenerative activity. Fibrils formed in the presence and absence of FN075 are indistinguishable on microscopic and macroscopic levels. Using small angle X-ray scattering, we reveal that FN075 induced oligomers are similar, but not identical, to oligomers previously observed during alpha-synuclein fibrillation. Since the levels of FN075 induced oligomers correlate with the amounts of fibrils among different FN075:protein ratios, the oligomers appear to be on-pathway and modeling supports an 'oligomer stacking model' for alpha-synuclein fibril elongation.
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Nors Perdersen
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Vito
authors.initials: V
authors.lastname: Foderà
authors.affiliation: Department of Chemistry, Umeå University, S-901 87 Umeå, Sweden.
authors.forename: Istvan
authors.initials: I
authors.lastname: Horvath
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Andreas
authors.initials: A
authors.lastname: van Maarschalkerweerd
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Katrine
authors.initials: K
authors.lastname: Nørgaard Toft
authors.affiliation: Department of Chemistry, Umeå University, S-901 87 Umeå, Sweden.
authors.forename: Christoph
authors.initials: C
authors.lastname: Weise
authors.affiliation: 1] Department of Chemistry, Umeå University, S-901 87 Umeå, Sweden [2] Umeå Centre for Microbial Research, Umeå University, 901 87 Umeå Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Almqvist
authors.affiliation: Department of Chemistry, Umeå University, S-901 87 Umeå, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Wolf-Watz
authors.affiliation: Department of Chemistry, Umeå University, S-901 87 Umeå, Sweden.
authors.forename: Pernilla
authors.initials: P
authors.lastname: Wittung-Stafshede
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Bente
authors.initials: B
authors.lastname: Vestergaard
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D058227:Amyloidogenic Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D066263:Protein Aggregation, Pathological / Q000378:metabolism; D017433:Protein Structure, Secondary; D011728:Pyridones / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000682:Amyloid; D058227:Amyloidogenic Proteins; D008024:Ligands; D011728:Pyridones; D051844:alpha-Synuclein; C017679:2-hydroxypyridine