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bioRxiv · 10.1101/295782

Phospholipid membranes promote the early stage assembly of α-synuclein aggregates

Lv, Z.·Hashemi, M.·Banerjee, S.·Zagorski, K.·Rochet, C.·Lyubchenko, Y. L.
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Abstract

Development of Parkinsons disease is associated with spontaneous self-assembly of -synuclein (-syn). Efforts aimed at understanding this process have produced little clarity and the mechanism remains elusive. We report a novel effect of phospholipid bilayers on the catalysis of -syn aggregation from monomers. We directly visualized -syn aggregation on supported lipid bilayers using time-lapse atomic force microscopy. We discovered that -syn assemble in aggregates on bilayer surfaces even at the nanomolar concentration of monomers in solution. The efficiency of the aggregation process depends on the membrane composition, being highest for a negatively charged bilayer. Furthermore, assembled aggregates can dissociate from the surface, suggesting that on-surface aggregation can be a mechanism by which pathological aggregates are produced. Computational modeling revealed that interaction of -syn with bilayer surface changes the protein conformation and its affinity to assemble into dimers, and these properties depend on the bilayer composition. A model of the membrane-mediated aggregation triggering the assembly of neurotoxic aggregates is proposed.

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Lv, Z., Hashemi, M., Banerjee, S., Zagorski, K., Rochet, C., Lyubchenko, Y. L.. 2018-04-05. Phospholipid membranes promote the early stage assembly of α-synuclein aggregates. https://doi.org/10.1101/295782

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