Structural basis of membrane disruption and cellular toxicity by a-synuclein oligomers

5 pags, 3 figsOligomeric species populated during the aggregation process of a-synuclein have been linked to neuronal impairment in Parkinson's disease and related neurodegenerative disorders. By using solution and solid-state nuclear magnetic resonance techniques in conjunction with other structural methods, we identified the fundamental characteristics that enable toxic a-synuclein oligomers to perturb biological membranes and disrupt cellular function; these include a highly lipophilic element that promotes strong membrane interactions and a structured region that inserts into lipid bilayers and disrupts their integrity. In support of these conclusions, mutations that target the region that promotes strong membrane interactions by a-synuclein oligomers suppressed their toxicity in neuroblastoma cells and primary cortical neurons.This research was supported by Parkinson's UK (G-1508 to G.F., M.V., C.M.D., and A.D.); the UK Medical Research Council (MR/N000676/1 to G.F., M.V. C.M.D., and A.D.); the Wellcome Trust (104933/2/14E to kD.): the Leverhulme Trust (RPG-2015-350 to A.D. and RPG-2015-345 to L.Y.); the British Heart Foundation (PG/14/93/31237 to A.D. and PG/11/81/29130 to L.Y.); the UK Biotechnology and Biological Sciences Research Council (BB/M023923/1 to A.D. and BB/G00594X/1 to L.Y.); the Agency of Science, Technology and Research of Singapore (to S.W.C.); the Ministry of Economy, Industry, and Competitiveness of Spain (MINECO RYC-2012-12068 and MINECO/FEDER EU BEU2015-64119-P to N.C.); the Regione Toscana (SUPREMAL to E.C., C.C., and R.C); the University of Florence (Eondi di Ateneo to E.C. and. C.C); and the Centre for Misfolding Diseases of the University of Cambridge. The data supporting the findings of this study are available within the article and supplementary materials.Peer reviewe