The neutral lipidome in Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disease with increasing evidence implicating lipid and fatty acid metabolism as important contributors to pathogenesis. Disrupted lipid metabolism, including sphingolipids, ceramides, cardiolipins, cholesterol, phospholipids and others, have been implicated in PD pathological processes, such as alpha-Synuclein (αS) aggregation, oxidative stress, and neuroinflammation. PD-associated dysregulation of neutral lipid metabolism is emerging as a key contributor to PD-associated lipid dyshomeostasis, prompting investigation of novel PD therapeutic targets and biomarkers in this pathway. However, PD-associated alterations of the human ‘neutral lipidome’ remains poorly understood, motivating this review. Herein, we comprehensively evaluate human studies reporting PD risk loci and concentrations of neutral lipids (triacylglycerols [TAGs], diacylglycerols [DAGs], monoacylglycerols [MAGs]) in samples from individuals with or without PD. Genetic and lipidomic evidence supports a dysregulated neutral lipidome in PD, as indicated by: (i) PD risk loci in or affecting neutral lipid metabolism pathways, (ii) PD-associated differences in neutral lipid concentrations in postmortem brain tissue and biofluids, (iii) meta-analysis-identified association between higher TAG concentrations and lower PD risk, (iv) PD candidate therapeutic targets in neutral lipid pathways, and (v) candidate neutral lipid PD biomarkers. Collectively, these data support the disruption of neutral lipid homeostasis as a contributing mechanism in PD. Thus, we propose the PD-associated neutral lipidome as an underexplored and important axis contributing to PD pathogenesis that can be targeted for the development of PD biomarkers and disease-modifying therapeutics.