Inhibition of aggregation and toxicity of α-synuclein in the presence of copper by an N-methylated peptide

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease. The aggregation of α-synuclein (α-syn) is characteristic of PD. Particularly, α-syn can bind to Cu2+ and the aggregation of α-syn is stimulated in the presence of Cu2+, which have attracted great attention. More importantly, recent studies have shown that the toxicity of α-syn aggregates significantly increases in the presence of Cu2+, which have led researchers to believe that α-syn−Cu2+ aggregates play a key role in PD. In this study, an N-methylated peptide (VAQKTmV) which derives from residues 77 to 82 of α-syn with an N-methylated valine at the C-terminal was synthesized and employed as an inhibitor to prevent the aggregation of α-syn−Cu2+. The inhibitory effect of VAQKTmV on α-syn−Cu2+ fibrillation was evaluated by ThT fluorescence assay, and confirmed by AFM analysis. Our results demonstrated that VAQKTmV can not only strongly inhibit the aggregation of α-syn−Cu2+, but also significantly prevent the α-syn−Cu2+-induced cytotoxicity toward SH-SY5Y cells. Our results suggest that VAQKTmV is a potential candidate for therapeutic treatment of PD.