Docosahexaenoic acid promotes vesicle clustering mediated by alpha-Synuclein via electrostatic interaction

alpha-Synuclein (alpha-Syn) is an intrinsically disordered protein whose aggregation is associated with Parkinson's disease, dementia, and other neurodegenerative diseases known as synucleinopathies. However, the functional role of alpha-Syn is still unclear, although it has been shown to be involved in the regulation of neurotransmitter release via the interaction with synaptic vesicles (SVs), vesicle clustering, and SNARE complex assembly. Fatty acids have significant occupancy in synaptic vesicles; and recent studies suggest the interaction of fatty acids with alpha-Syn affect the formation of (pathological) aggregates, but it is less clear how fatty acids affects the functional role of alpha-Syn including alpha-Syn-membrane interactions, in particular with (SV-like) vesicles. Here, we report the concentration dependent effect of docosahexaenoic acid (DHA) in synaptic-like vesicle clustering via alpha-Syn interaction. Through molecular dynamics simulation, we revealed that DHA promoted vesicle clustering is due to the electrostatic interaction between DHA in the membrane and the N-terminal region of alpha-Syn. Moreover, this increased electrostatic interaction arises from a change in the macroscopic properties of the protein-membrane interface induced by (preferential solvation of) DHA. Our results provide insight as to how DHA regulates vesicle clustering mediated by alpha-Syn and may further be useful to understand its physiological as well as pathological role.Graphical AbstractDescription: In physiological environments, alpha-Synuclein (alpha-Syn) localizes at nerve termini and synaptic vesicles and interacts with anionic phospholipid membranes to promote vesicle clustering. Docosahexaenoic acid (DHA) increases binding affinity between alpha-Syn and lipid membranes by increasing electrostatic interaction energy through modulating the local and global membrane environment and conformational properties of alpha-Syn.

Automated summary

In this study, we used molecular dynamics simulation to reveal that docosahexaenoic acid (DHA) enhances the binding affinity between α-Synuclein (α-Syn) and lipid membranes by increasing electrostatic interaction energy. This promotes synaptic-like vesicle clustering via α-Syn interaction. Our findings provide insights into how DHA regulates α-Syn-mediated vesicle clustering, shedding light on its physiological and pathological role.