The modification of α-synuclein by dicarbonyl compounds inhibits its fibril-forming process

Abstract

Oxidative modification of α-synuclein (αSyn) was reported to have significant effects on its amyloidogenic properties. Dicarbonyl compounds are metabolites accumulated by various oxidative processes in the intracellular environment. In this study, two dicarbonyl compounds, methylglyoxal (MGO) and glyoxal (GO), were investigated for their effects on the structural and fibril-forming properties of αSyn. Both compounds were found to induce the oligomerization of αSyn. By adding substoichiometric amounts of αSyn modified by MGO or GO, the fibrillization of αSyn was substantially inhibited. The heterogeneously-modified αSyns were separated into three fractions: monomers, oligomers, and high molecular mass oligomers. When each modified αSyn species was used to seed fibril formation, protein fibrillization was significantly suppressed. Temperature scanning and interactions with liposomes revealed that both MGO- and GO-modified monomers were not as susceptible as the unmodified αSyn to conformational changes into partially folded intermediates and α-helixes. Our observations suggest that dicarbonyl modification of αSyn reduces conformational flexibility of the protein, thereby contributing to a reduction in the ability of αSyn to form fibrils, and the modified protein inhibits the fibrillization of the unmodified αSyn.