Brain-region-specific lipid dysregulation in L-DOPA-induced dyskinesia in a primate model of Parkinson's disease.

Kaya I, Vallianatou T, Nilsson A, Bjärterot P, Shariatgorji R, Svenningsson P, Bezard E, Andrén PE

NPJ Parkinsons Dis 11 (1) 258 [2025-08-23; online 2025-08-23]

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.

Spatial Mass Spectrometry [Technology development]

PubMed 40849420

DOI 10.1038/s41531-025-01109-6

Crossref 10.1038/s41531-025-01109-6

pmc: PMC12374971
pii: 10.1038/s41531-025-01109-6