Peculiar hydrophobic properties of the 67-78 fragment of α-synuclein are responsible for membrane destabilization and neurotoxicity

α-synuclein is a 140 residue protein linked to Parkinson’s disease. Intraneural inclusions called Lewy bodies and Lewy neurites are mainly composed of α-synuclein aggregated in amyloid fibrils. Few years ago, tilted peptides have been detected in two other amyloidogenic proteins : the amyloid β peptide involved in Alzheimer’s disease, and the PrP protein linked to Creuztfeldt-Jakob’s disease. Tilted peptides are short protein fragments that adopt an oblique orientation when inserted into biological membranes. Tilted peptides are able to destabilize membranes. In this study, we predicted by sequence analysis and molecular modelling that the 67-78 fragment of α-synuclein is a tilted peptide. Like most of them, the α-syn 67-78 peptide is able to induce lipid mixing and leakage of unilamellar liposomes. A mutant designed by molecular modelling to decrease the destabilizing properties of the peptide was shown to be significantly less fusogenic. The neuronal toxicity was studied using human neuroblastoma cells and we demonstrated that the α-syn 67-78 peptide induces neurotoxicity. In conclusion, we have identified a tilted peptide in α-synuclein which could be involved in the toxicity induced during amyloidogenesis of α-synuclein.