Lipid Dysregulation and Impaired Resolution of Inflammation in Genetic Forms of Parkinson’s Disease: Potential Links and Knowledge Gaps

Dysregulation of lipid metabolism plays an important role in the development of Parkinson’s disease (PD), particularly in PD monogenic forms. At the same time, accumulating evidence points to impaired resolution of neuroinflammation mediated by specialized pro-resolving mediators (SPMs), although mutation-specific data remain limited. Mutations in PD-associated genes, such as GBA1, LRRK2, SNCA, PLA2G6 and others, are linked to lipidomic changes, including altered sphingolipid, phospholipid, and polyunsaturated fatty acid profiles in plasma membranes, organelle membranes, and extracellular vesicles. These disturbances influence membrane composition, fluidity, and dynamics, and may also affect the biosynthesis and activity of SPMs. Importantly, the nature of lipid metabolism dysregulation appears to be mutation-specific and may differentially impact SPM biosynthetic pathways and the availability of SPM receptors, and downregulate SPM signaling, leading to heterogeneous inflammatory phenotypes across genetic forms of PD. Here, we attempt to trace potential links between lipid metabolic dysfunction and disruption of SPM functioning in genetic PD, with a focus on mutation-specific changes. This integrated view may provide new insights into PD mechanisms and guide the development of mutation-specific therapeutic approaches aimed at restoring pro-resolving lipid signaling in genetically defined forms of the disease.