Shared and distinct lipid profiles in amygdala from sporadic and GBA-associated Parkinson's diseases

Parkinson's Disease (PD) is a neurodegenerative disorder characterised by the deposition of protein-lipid inclusions, containing alpha-synuclein, neuronal cell loss and disruptions in lipid metabolism. GBA mutations are together an important genetic risk factor for PD and are associated with a decrease in glucocerebrosidase, a lysosomal glycoprotein encoded by GBA, an increase in alpha-synuclein and changes in the levels of glucocerebrosidase's substrates, glucosylsphingosine and glucosylceramide, and some sphingolipids. In this study, we found extensive metabolic remodelling of lipids, beyond glucocerebrosidase's substrates, in the amygdala from people with sPD and disease duration above 30 years (sPD_>30y) and from people with PD carriers of a GBA risk mutation (PD-GBA_risk). Besides increases in glucosylceramide and sphingolipid levels, we observed increased free cholesterol, diacylglyceride and most glycerophospholipids in these samples relative to healthy controls. Moreover, we found a shift from short to long sphingomyelin and ceramide and from long to short phosphatidylserine and phosphatidylethanolamine in sPD_>30y and PD-GBA_risk cases, and the opposite in PD-GBA_severe cases. The levels of lipid classes and the relative proportion of lipid species affected in PD amygdala all correlated with glucocerebrosidase activity and/or pathological alpha-synuclein levels. The distinct lipid phenotypes observed across PD subgroups underscore the importance of patient stratification in clinical trials aiming at reverting PD-related lipid changes.