Objective: To identify early lipid alterations in a progressive mouse model of Parkinson’s disease (PD) and to determine whether peripheral lipid signatures reflect lipid changes in the midbrain.

Background: Lipid metabolism is increasingly recognized as a key contributor to PD pathology. Although post-mortem studies have reported disease-specific lipid alterations in advanced PD, it remains unclear whether these changes emerge early during disease progression and whether peripheral lipid profiles mirror central nervous system (CNS) lipid dysregulation. Addressing this gap is critical for understanding early pathogenic mechanisms and for developing accessible biomarkers.

Method: A progressive mouse model of α-synuclein pre-formed fibril (PFF)–induced pathology was employed. Male and female mice received unilateral PFF injections into the substantia nigra and were analysed three months post-injection. Dopaminergic neuron integrity was assessed by immunohistochemistry. Lipids were extracted from midbrain tissue and plasma and analysed using HPLC–Q-TOF–MS. Untargeted lipidomics was performed on midbrain samples, while targeted lipidomic analysis was conducted on plasma. Data processing, pathway enrichment, and network analyses were performed using MetaboAnalyst 6.0.

Results: PFF-injected mice exhibited approximately 24% dopaminergic neuron loss accompanied by mild motor deficits. Midbrain lipidomics revealed significant upregulation of fatty acid, steroid, and glycerophospholipid biosynthesis pathways, along with a modest increase in sphingomyelin metabolism. Network analysis identified disruptions in monoacylglycerol-mediated fatty acid metabolism. Plasma lipidomics showed similar but less pronounced alterations in fatty acid profiles and sphingolipid metabolism, suggesting partial concordance with CNS lipid changes.

Conclusion: Our findings demonstrate that early PD pathology is associated with coordinated disturbances in sphingolipid metabolism, fatty acid turnover, and steroid biosynthesis. Consistent dysregulation of sphingolipid and monoacylglycerol pathways across midbrain and plasma highlights ceramide–sphingomyelin dyshomeostasis and altered lipid handling as early contributors to PD. The partial overlap between central and peripheral lipid signatures supports the potential of plasma lipidomics for early biomarker discovery and identifies lipid metabolic pathways as promising therapeutic targets.

« Back to 2026 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/lipid-alterations-in-central-nervous-system-and-plasma-during-early-stages-of-parkinsons-disease/