Lipid pathway dysfunction is prevalent in patients with Parkinson's disease

• Published in: Brain (London, England : 1878) England : 1878), 2022-10, Vol.145 (10), p.3472-3487
• Main Authors: Galper, Jasmin, Dean, Nicholas J, Pickford, Russell, Lewis, Simon J G, Halliday, Glenda M, Kim, Woojin S, Dzamko, Nicolas
• Format: Article
• Language: English
• Subjects: Original
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awac176

Many genetic risk factors for Parkinson's disease have lipid-related functions and lipid-modulating drugs such as statins may be protective against Parkinson's disease. Moreover, the hallmark Parkinson's disease pathological protein, α-synuclein, has lipid membrane function and pathways dysregulated in Parkinson's disease such as the endosome-lysosome system and synaptic signaling rely heavily on lipid dynamics. Despite the potential role for lipids in Parkinson's disease, most research to date has been protein-centric, with large-scale, untargeted serum and CSF lipidomic comparisons between genetic and idiopathic Parkinson's disease and neurotypical controls limited. In particular, the extent to which lipid dysregulation occurs in mutation carriers of one of the most common Parkinson's disease risk genes, LRRK2, is unclear. Further, the functional lipid pathways potentially dysregulated in idiopathic and LRRK2 mutation Parkinson's disease is underexplored. To better determine the extent of lipid dysregulation in Parkinson's disease, untargeted high performance liquid chromatography-tandem mass spectrometry was performed on serum (N = 221) and CSF (N = 88) obtained from a multiethnic population from the Michael J Fox Foundation LRRK2 Clinical Cohort Consortium. The cohort consisted of controls, asymptomatic LRRK2 G2019S carriers, LRRK2 G2019S carriers with Parkinson's disease and Parkinson's disease patients without a LRRK2 mutation. Age and sex were adjusted for in analyses where appropriate. Approximately one thousand serum lipid species per participant were analyzed. The main serum lipids that distinguished both Parkinson's disease patients and LRRK2 mutation carriers from controls included species of ceramide, triacylglycerol, sphingomyelin, acylcarnitine, phosphatidylcholine and lysophosphatidylethanolamine. Significant alterations in sphingolipids and glycerolipids were also reflected in Parkinson's disease and LRRK2 mutation carrier CSF, although no correlations were observed between lipids identified in both serum and CSF. Pathway analysis of altered lipid species indicated that sphingolipid metabolism, insulin signaling and mitochondrial function were the major metabolic pathways dysregulated in Parkinson's disease. Importantly, these pathways were also found to be dysregulated in serum samples from a second Parkinson's disease cohort (N = 315). Results from this study demonstrate that dysregulated lipids in Parkinson's disease generally, and in L