title: High stability and cooperative unfolding of α-synuclein oligomers.
abstract: Many neurodegenerative diseases are linked with formation of amyloid aggregates. It is increasingly accepted that not the fibrils but rather oligomeric species are responsible for degeneration of neuronal cells. Strong evidence suggests that in Parkinson's disease (PD), cytotoxic α-synuclein (αSN) oligomers are key to pathogenicity. Nevertheless, insight into the oligomers' molecular properties remains scarce. Here we show that αSN oligomers, despite a large amount of disordered structure, are remarkably stable against extreme pH, temperature, and even molar amounts of chemical denaturants, though they undergo cooperative unfolding at higher denaturant concentrations. Mutants found in familial PD lead to slightly larger oligomers whose stabilities are very similar to that of wild-type αSN. Isolated oligomers do not revert to monomers but predominantly form larger aggregates consisting of stacked oligomers, suggesting that they are off-pathway relative to the process of fibril formation. We also demonstrate that 4-(dicyanovinyl)julolidine (DCVJ) can be used as a specific probe for detection of αSN oligomers. The high stability of the αSN oligomer indicates that therapeutic strategies should aim to prevent the formation of or passivate rather than dissociate this cytotoxic species.
authors.affiliation: Interdisciplinary Nanoscience Center (iNANO), Aarhus University , Gustav Wieds Vej 14, DK - 8000 Aarhus C, Denmark.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Paslawski
authors.forename: Maria
authors.initials: M
authors.lastname: Andreasen
authors.forename: Søren Bang
authors.initials: SB
authors.lastname: Nielsen
authors.forename: Nikolai
authors.initials: N
authors.lastname: Lorenzen
authors.forename: Karen
authors.initials: K
authors.lastname: Thomsen
authors.forename: Jørn Døvling
authors.initials: JD
authors.lastname: Kaspersen
authors.forename: Jan Skov
authors.initials: JS
authors.lastname: Pedersen
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Otzen
mesh_terms: D000682:Amyloid / Q000737:chemistry; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D006863:Hydrogen-Ion Concentration; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D055550:Protein Stability; D058767:Protein Unfolding; D053838:Scattering, Small Angle; D017550:Spectroscopy, Fourier Transform Infrared; D013696:Temperature; D014961:X-Ray Diffraction; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D000682:Amyloid; D051844:alpha-Synuclein