Multi-omic analysis reveals lipid dysregulation associated with mitochondrial dysfunction in parkinson’s disease brain

Parkinson's disease (PD) is an increasingly prevalent neurodegenerative disorder, largely sporadic in origin, with limited understanding of age- and region-specific lipid alterations in the human brain. Dysregulation of glycosphingolipid catabolism has been implicated in PD, yet comprehensive spatiotemporal profiling remains sparse. Here, we performed targeted lipidomics across eight anatomically distinct brain regions in post-mortem controls, mid-stage, and late-stage PD cases using high-precision tissue dissection. Each region displayed distinct lipid signatures, with several age-associated alterations-most notably in hexosylceramides, including glucosylceramide. In PD, glycosphingolipids were reduced in subcortical regions but elevated in cortical regions, particularly gangliosides, HexCer, and Hex2Cer, accompanied by increased sphingolipids and decreased phospholipids. The most pronounced mid-stage changes occurred in the putamen, where very long chain ceramide species and plasmalogen PE decreased, then normalising in late-stage disease. Lyso-phosphatidylcholine increased progressively throughout PD progression. Integrating proteomic data, we observed sphingomyelin levels associated with PD-related proteins, while dysregulated mitochondrial function correlated with antioxidant plasmalogens, long-chain ceramides, lyso-phosphatidylcholine, and HexCer in the putamen. These findings highlight region- and stage-specific lipid alterations in PD and their potential convergence with mitochondrial dysfunction.