The modification of alpha-synuclein by dicarbonyl compounds inhibits its fibril-forming process.
Oxidative modification of alpha-synuclein (alphaSyn) 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 alphaSyn. Both compounds were found to induce the oligomerization of alphaSyn. By adding substoichiometric amounts of alphaSyn modified by MGO or GO, the fibrillization of alphaSyn was substantially inhibited. The heterogeneously-modified alphaSyns were separated into three fractions: monomers, oligomers, and high molecular mass oligomers. When each modified alphaSyn 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 alphaSyn to conformational changes into partially folded intermediates and alpha-helixes. Our observations suggest that dicarbonyl modification of alphaSyn reduces conformational flexibility of the protein, thereby contributing to a reduction in the ability of alphaSyn to form fibrils, and the modified protein inhibits the fibrillization of the unmodified alphaSyn.
Lee
Daekyun
D
Department of Life Science, Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, 790-784, Republic of Korea.
Park
Chang Wook
CW
Paik
Seung R
SR
Choi
Kwan Yong
KY
D045744:Cell Line, Tumor; D002942:Circular Dichroism; D017127:Glycation End Products, Advanced / Q000737:chemistry; D006037:Glyoxal / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008081:Liposomes / Q000494:pharmacology; D010084:Oxidation-Reduction; D011487:Protein Conformation; D020836:Protein Structure, Quaternary; D011765:Pyruvaldehyde / Q000378:metabolism*; D013696:Temperature; D051844:alpha-Synuclein / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism
D017127:Glycation End Products, Advanced; D008081:Liposomes; D051844:alpha-Synuclein; D006037:Glyoxal; D011765:Pyruvaldehyde