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

Abstract

`Oxidative modification of alpha-synuclein (alpha Syn) 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 alpha Syn. Both compounds were found to induce the oligomerization of alpha Syn. By adding substoichiometric amounts of alpha Syn modified by MGO or GO, the fibrillization of alpha Syn was substantially inhibited. The heterogeneously-modified alpha Syns were separated into three fractions: monomers, oligomers, and high molecular mass oligomers. When each modified alpha Syn 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 alpha Syn to conformational changes into partially folded intermediates and alpha-helixes. Our observations suggest that dicarbonyl modification of (alpha Syn reduces conformational flexibility of the protein. thereby contributing to a reduction in the ability of alpha Syn to form fibrils, and the modified protein inhibits the fibrillization of the unmodified alpha Syn. (C) 2008 Elsevier B.V. All rights reserved.