biostudies-literatureKaya IVetenskapsrådetAgence Nationale de la RechercheHjärnfonden258https://www.ebi.ac.uk/biostudies/studies/S-EPMC12374971biostudies-literatureUnknown11(1)L-DOPA-induced dyskinesia (LID) is a significant and treatment-limiting complication in Parkinson's disease (PD) therapy, yet its mechanisms remain poorly understood. We used high-resolution mass spectrometry imaging to map brain-region-specific alterations of glycerophospholipids and sphingolipids in a female macaque model of PD with and without LID following chronic L-DOPA treatment. LID was associated with depletion of antioxidant plasmalogen phosphatidylcholines in the globus pallidus interna, claustrum, and precentral gyrus-regions critical for motor function-and elevations of polyunsaturated fatty acid-containing glycerophospholipids, indicative of increased membrane fluidity. This lipid profile differed from similarly treated non-dyskinetic animals, suggesting lipid composition mediates differential susceptibility to LID. Lipid alterations correlated strongly with dyskinesia severity, dopamine, and L-DOPA concentrations, supporting a mechanistic link between lipid metabolism, neurotransmitter dysregulation, and LID. This comprehensive spatial lipidomic analysis identifies region-specific lipid dysregulation as a novel aspect of LID pathology, highlighting lipid pathways as potential therapeutic targets for mitigating dyskinesia.NPJ Parkinson's diseaseBrain-region-specific lipid dysregulation in L-DOPA-induced dyskinesia in a primate model of Parkinson's disease.PMC123749712021-03293ANR-07-MNP TRAFINLIDFO2021-0318Vallianatou TShariatgorji RBjarterot PAndren PEKaya INilsson ASvenningsson PBezard EfalseBrain-region-specific lipid dysregulation in L-DOPA-induced dyskinesia in a primate model of Parkinson's disease.L-DOPA-induced dyskinesia (LID) is a significant and treatment-limiting complication in Parkinson's disease (PD) therapy, yet its mechanisms remain poorly understood. We used high-resolution mass spectrometry imaging to map brain-region-specific alterations of glycerophospholipids and sphingolipids in a female macaque model of PD with and without LID following chronic L-DOPA treatment. LID was associated with depletion of antioxidant plasmalogen phosphatidylcholines in the globus pallidus interna, claustrum, and precentral gyrus-regions critical for motor function-and elevations of polyunsaturated fatty acid-containing glycerophospholipids, indicative of increased membrane fluidity. This lipid profile differed from similarly treated non-dyskinetic animals, suggesting lipid composition mediates differential susceptibility to LID. Lipid alterations correlated strongly with dyskinesia severity, dopamine, and L-DOPA concentrations, supporting a mechanistic link between lipid metabolism, neurotransmitter dysregulation, and LID. This comprehensive spatial lipidomic analysis identifies region-specific lipid dysregulation as a novel aspect of LID pathology, highlighting lipid pathways as potential therapeutic targets for mitigating dyskinesia.2025-01-01T00:00:00Z2025 Aug2026-05-09T17:59:55.269Z2026-04-08T01:08:54.34ZS-EPMC123749714084942010.1038/s41531-025-01109-6