Lipid membrane remodeling by myristic acid treatment reverses Parkinson's disease α-synuclein phenotypes in patient neurons.
Lipid membrane remodeling by myristic acid treatment reverses Parkinson's disease α-synuclein phenotypes in patient neurons.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Cambridge, US · Author affiliation
Broad Institute of MIT and Harvard, Cambridge, MA, USA.Location evidence
Boston, US · Author affiliation
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.Location evidence
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Original abstract
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.