N-acetylation of α-synuclein enhances synaptic vesicle clustering mediated by α-synuclein and lysophosphatidylcholine

Post-translational modifications (PTMs) of -synuclein (-syn) such as acetylation and phosphorylation play important yet distinct roles in regulating -syn conformation, membrane binding, and amyloid aggregation. However, how PTMs regulate -syn function in presynaptic terminals remains unclear. Previously, we reported that -syn clusters synaptic vesicles (SV)1, and neutral phospholipid lysophosphatidylcholine (LPC) can mediate this clustering2. Here, based on our previous findings, we further demonstrate that N-terminal acetylation, which occurs under physiological conditions and is irreversible in mammalian cells, significantly enhances the functional activity of -syn in clustering SVs. Mechanistic studies reveal that this enhancement is caused by the N-acetylation-promoted insertion of -syns N-terminus and increased intermolecular interactions on the LPC-containing membrane. Our work demonstrates that N-acetylation fine-tunes -syn-LPC interaction for mediating -syns function in SV clustering.