Dysregulated metabolism of ceramides and glycosphingolipids in Parkinson’s disease

Alterations in sphingolipid metabolism have been implicated in the pathogenesis of Parkinson's disease (PD), yet findings regarding peripheral sphingolipid changes remain inconsistent. This study aimed to elucidate the metabolic profiles of plasma ceramides and glycosphingolipids (GSLs) in patients with PD. We recruited 250 patients with PD and 250 age- and sex-matched neurologically healthy controls. Plasma ceramide and GSL species were quantified using liquid chromatography‒tandem mass spectrometry, complemented by a meta-analysis of the gene expression levels of relevant enzymes in the substantia nigra obtained from Gene Expression Omnibus. A total of 119 sphingolipids were analyzed. Significant differences in plasma sphingolipid species were observed, including increased GSLs and decreased dihydroceramides. Incorporation of 35 significantly altered sphingolipid species enabled discrimination of patients with PD from controls with an AUC of 0.80 (P < 0.0001). Notable alterations in lipid ratios were detected, with increases in the monohexosylceramide-to-ceramide ratio as well as the monosialodihexosylganglioside-to-dihexosylceramide and trihexosylceramide-to-dihexosylceramide ratios. We also observed a higher ceramide-to-dihydroceramide ratio and shifts in ceramide characteristics, reflecting changes in the ceramide synthesis pathway. Supporting these findings, meta-analysis revealed changes in the expression of relevant enzymes, including decreased expression of lysosomal hydrolases, such as β-glucocerebrosidase and α-galactosidase, reinforcing the impaired GSL degradation and alteration in ceramide synthesis observed in PD. Our results suggest that altered peripheral ceramide and GSL profiles can discriminate PD from controls. Moreover, we highlight disrupted GSL and ceramide metabolism in PD patients, emphasizing the need for further research to explore the implications of these metabolic disturbances in PD pathogenesis.