Treating Parkinson's patient neurons with myristic acid (C14:0) remodels membrane lipid composition, reduces pathogenic α-synuclein membrane association, lowers Lewy-like inclusions and pSer129, and restores tetramer:monomer balance, with NMR showing decreased membrane dwell time and aggregation…

Provides a clear, actionable mechanism—lipid remodeling via C14:0—that reverses α-synuclein pathogenic phenotypes in patient neurons and offers a plausible translational path for lipid-based or metabolic therapies in PD.

Despite the lipid-rich nature of the brain, defining the role of lipid metabolism in neurodegenerative disease and targeting lipid metabolic pathways for disease modification are in their infancy. In Parkinson's disease, Lewy body dementia, and other synucleinopathies, disease-associated forms of α-synuclein (αS) alter fatty acid (FA) metabolism, increasing monounsaturated FA-containing lipids. This disequilibrium in membrane fatty acyl composition results in aberrant αS:membrane interactions. We report treating PD patient neurons with myristic acid (C14:0) induces lipid metabolism modifications correcting abnormal PD-associated membrane composition and reversing PD-relevant phenotypes. C14:0 conditioning reduced Lewy-like αS inclusions; reduced abnormal pSer129 αS; corrected excess αS at membranes; and restored native αS tetramer:monomer homeostasis. Using nuclear magnetic resonance, we established C14:0 as correcting abnormal αS vesicle membranes dwell time in vitro, correlating with less pathogenic αS aggregation. Mechanistically, C14:0 rescued PD neuron phenotypes through remodeling the PD-associated lipidome, eliciting beneficial effects by increasing shorter, saturated fatty acyl-lipids.