α-Synuclein (α-syn) is a 140-residue intrinsically disordered protein that is involved in neuronal and synaptic vesicle plasticity, but its aggregation to form amyloid fibrils is the hallmark of Parkinson's disease (PD). The interaction between α-syn and lipid surfaces is believed to be a key feature for mediation of its normal function, but under other circumstances it is able to modulate amyloid fibril formation. Using a combination of experimental and theoretical approaches, we identify the mechanism through which facile aggregation of α-syn is induced under conditions where it binds a lipid bilayer, and we show that the rate of primary nucleation can be enhanced by three orders of magnitude or more under such conditions. These results reveal the key role that membrane interactions can have in triggering conversion of α-syn from its soluble state to the aggregated state that is associated with neurodegeneration and to its associated disease states.
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We wish to thank M. Ouberai for her help with the preparation of SUVs and for valuable discussions along with C. Waudby and J. Christodoulou. This work was supported by the UK Biotechnology and Biochemical Sciences Research Council (BB/H003843/1 to C.M.D. and M.V.); the Wellcome Trust (094425/Z/10/Z to C.M.D., T.P.J.K. and M.V.); the European Research Council (337969, T.P.J.K.); the Frances and Augustus Newman Foundation (T.P.J.K.); Magdalene College, Cambridge (A.K.B.); St John's College, Cambridge (T.C.T.M.); the Cambridge Home and EU Scholarship Scheme (G.M.); Elan Pharmaceuticals (C.M.D., T.P.J.K., M.V., C.G. and A.K.B.) and the Leverhulme Trust (A.K.B.).
The authors declare no competing financial interests.
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Galvagnion, C., Buell, A., Meisl, G. et al. Lipid vesicles trigger α-synuclein aggregation by stimulating primary nucleation. Nat Chem Biol 11, 229–234 (2015). https://doi.org/10.1038/nchembio.1750
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