Inhibition of fibril formation and toxicity of a fragment of α-synuclein by an N-methylated peptide analogue

α-Synuclein has been linked to amyloidogenesis in Parkinson's disease and other neurodegenerative disorders. We have previously shown that a peptide comprising residues 68–78 of α-synuclein is the minimum fragment that, like α-synuclein itself, forms amyloid fibrils and exhibits toxicity towards cells in culture. Hughes et al. [J. Biol. Chem. 275 (2000) 25109] showed that an N-methylated derivative of Aβ(25–35) inhibited the formation of fibrils by Aβ(25–35) and reduced its toxicity. We have now extended this concept to an amyloidogenic α-synuclein-based peptide. α-Synuclein(68–78), N-methylated at G1y73, was compared to non-methylated peptide. Whereas α-synuclein(68–78) formed fibrils and was toxic to cells, the N-methylated analogue had neither of these properties. Moreover, an equimolar mixture of the non-methylated and methylated peptides formed very few fibrils and toxicity was markedly reduced.