The role of stable α-synuclein oligomers in the molecular events underlying amyloid formation

Nikolai Lorenzen, Søren Bang Nielsen, Alexander K. Buell, Jørn Døvling Kaspersen, Paolo Arosio, Brian Stougaard Vad, Wojciech Paslawski, Gunna Christiansen, Zuzana Valnickova Hansen, Maria Andreasen, Jan Johannes Enghild, Jan Skov Pedersen, Christopher M Dobson, Tuomas P J Knowles, Daniel Otzen

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review


Studies of protein amyloid formation 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 (SAXS) 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.
Original languageEnglish
JournalJournal of the American Chemical Society
Pages (from-to)3859-3868
Number of pages10
Publication statusPublished - 16 Feb 2014


  • synuclein
  • aggregation
  • amyloid fibril
  • elongation
  • growth


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