High stability and cooperative unfolding of cytotoxic α-synuclein oligomers

TY - JOUR

T1 - High stability and cooperative unfolding of cytotoxic α-synuclein oligomers

AU - Paslawski, Wojciech

AU - Andreasen, Maria

AU - Nielsen, Søren Bang

AU - Lorenzen, Nikolai

AU - Thomsen, Karen

AU - Kaspersen, Jørn Døvling

AU - Pedersen, Jan Skov

AU - Otzen, Daniel

PY - 2014/9/12

Y1 - 2014/9/12

N2 - 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.

AB - 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.

U2 - 10.1021/bi5007833

DO - 10.1021/bi5007833

M3 - Journal article

C2 - 25216651

SN - 0006-2960

VL - 53

SP - 6252

EP - 6263

JO - Biochemistry

JF - Biochemistry

IS - 39

ER -