title: The role of stable α-synuclein oligomers in the molecular events underlying amyloid formation.
abstract: Studies of proteins' formation of amyloid fibrils have revealed that potentially cytotoxic oligomers frequently accumulate during fibril formation. An important question in the context of mechanistic studies of this process is whether or not oligomers are intermediates in the process of amyloid fibril formation, either as precursors of fibrils or as species involved in the fibril elongation process or instead if they are associated with an aggregation process that is distinct from that generating mature fibrils. Here we describe and characterize in detail two well-defined oligomeric species formed by the protein α-synuclein (αSN), whose aggregation is strongly implicated in the development of Parkinson's disease (PD). The two types of oligomers are both formed under conditions where amyloid fibril formation is observed but differ in molecular weight by an order of magnitude. Both possess a degree of β-sheet structure that is intermediate between that of the disordered monomer and the fully structured amyloid fibrils, and both have the capacity to permeabilize vesicles in vitro. The smaller oligomers, estimated to contain ∼30 monomers, are more numerous under the conditions used here than the larger ones, and small-angle X-ray scattering data suggest that they are ellipsoidal with a high degree of flexibility at the interface with solvent. This oligomer population is unable to elongate fibrils and indeed results in an inhibition of the kinetics of amyloid formation in a concentration-dependent manner.
authors: Department of Molecular Biology, Center for Insoluble Protein Structures (inSPIN) and §Department of Chemistry, Interdisciplinary Nanoscience Center (iNANO), Aarhus University , Gustav Wieds Vej 14, 8000 Aarhus C, Denmark.
authors: Nikolai
authors: N
authors: Lorenzen
authors: Søren Bang
authors: SB
authors: Nielsen
authors: Alexander K
authors: AK
authors: Buell
authors: Jørn Døvling
authors: JD
authors: Kaspersen
authors: Paolo
authors: P
authors: Arosio
authors: Brian Stougaard
authors: BS
authors: Vad
authors: Wojciech
authors: W
authors: Paslawski
authors: Gunna
authors: G
authors: Christiansen
authors: Zuzana
authors: Z
authors: Valnickova-Hansen
authors: Maria
authors: M
authors: Andreasen
authors: Jan J
authors: JJ
authors: Enghild
authors: Jan Skov
authors: JS
authors: Pedersen
authors: Christopher M
authors: CM
authors: Dobson
authors: Tuomas P J
authors: TP
authors: Knowles
authors: Daniel Erik
authors: DE
authors: Otzen
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007700:Kinetics; D010300:Parkinson Disease / Q000378:metabolism; D066329:Protein Aggregates; D011487:Protein Conformation; D055503:Protein Multimerization; D053838:Scattering, Small Angle; D014961:X-Ray Diffraction; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D000682:Amyloid; D066329:Protein Aggregates; D051844:alpha-Synuclein