Aarhus University Seal

High stability and cooperative unfolding of cytotoxic α-synuclein oligomers

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

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 SN 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 SN. 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 SN oligomer indicates that therapeutic strategies should aim to prevent the formation or passivate rather than dissociate this cytotoxic species.

Original languageEnglish
Pages (from-to)6252-6263
Number of pages12
Publication statusPublished - 12 Sep 2014

See relations at Aarhus University Citationformats

ID: 81582669