Assembly of α-synuclein aggregates on phospholipid bilayers

The spontaneous self-assembly of alpha-synuclein (alpha-syn) into aggregates of different morphologies is associated with the development of Parkinson's disease. However, the mechanism behind the spontaneous assembly remains elusive. The current study shows a novel effect of phospholipid bilayers on the assembly of the alpha-syn aggregates. Using time-lapse atomic force microscopy, it was discovered that alpha-syn assembles into aggregates on bilayer surfaces, even at the nanomolar concentration range. The efficiency of the aggregation process depends on the membrane composition, with the greatest efficiency observed for of 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (POPS). Importantly, assembled aggregates can dissociate from the surface, suggesting that on surface aggregation is a mechanism by which pathological aggregates may be produced. Computational modeling revealed that dimers of alpha-syn assembled rapidly, through the membrane-bound monomer on POPS bilayer, due to an aggregation-prone orientation of alpha-syn. Interaction of alpha-syn with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) leads to a binding mode that does not induce a fast assembly of the dimer. Based on these findings, we propose a model in which the interaction of alpha-syn with membranes plays a critical role initiating the formation of alpha-syn aggregates and the overall aggregation process.