Lipidomic Profiling Reveals Shared and Distinct Pathological Signatures in Sporadic Parkinson’s Disease and GBA Mutation Carriers: Implications for Disease Mechanisms

Parkinson’s Disease (PD) is a neurodegenerative disorder characterised by the deposition of protein inclusions, called Lewy Bodies (LBs), in neurons. LBs are heterogeneous structures whose main constituent is the protein alpha-synuclein (αS) and that are also composed of lipid molecules. Disruptions in the levels of specific lipids, including sphingolipids, fatty acids, and cholesterol, have been associated with PD, suggesting a role of lipids in the emergence and spreading of αS and PD pathology. Using a combination of shotgun lipidomics and biochemical analyses of PD amygdala homogenates, we have shown that long sporadic disease duration and GBA risk mutation are associated with a decrease in the protein and activity levels of glucocerebrosidase (GCase) activity and in cardiolipin levels and an increase in those of pathological αS, cholesterol, diacylglycerides, sphingolipids and specific glycerophospholipids (GPL). Long sporadic PD and GBA risk mutations also led to a shift from long unsaturated to short saturated GPL and from short to long sphingomyelin and ceramide. Moreover, the levels of lipid classes and species affected by long sPD and GBA risk mutations were found to correlate negatively with GCase activity and positively with pathological αS levels. We found that GBA mutation with mild phenotype affects lipid levels in the same direction as GBA risk mutation and long sPD but to a lesser extent and that GBA mutation carriers with severe phenotype led to changes in the opposite direction for the same lipids. Finally, the lipid analyses of LB- and small aggregates enriched fractions show that long sPD and GBA risk mutations led to the same changes in the levels and species distribution of GPL and SL than in homogenates but to a lesser extent. Together, these results suggest the need for patient stratification in clinical trials of therapeutic interventions in PD-GBA and that successful therapeutics against PD-GBA should be considered for sporadic PD.