The Emerging Parkinson's Disease Oxylipin‐Ome

ABSTRACT Parkinson Disease (PD) is increasingly considered a proteinopathy and lipidopathy. This proteinopathy+lipidopathy paradigm has been further refined to a fatty acid (FA)‐opathy, centering dysregulated FA metabolism as fundamental in PD lipid dysfunction. FA dysfunction can disrupt alpha‐synuclein (αS)‐membrane interactions, altering αS localization, conformation, and aggregation. Correcting FA dyshomeostasis rescues PD‐associated αS phenotypes and is a promising strategy for disease‐modifying therapeutics. Herein, we consider the impact of PD FA dyshomeostasis in modifying the bioactive oxylipin‐ome. Oxylipin metabolism is complex, and the role of oxylipins in PD is not yet fully determined. This perspective considers PD‐associated differences oxylipin profiles, oxylipin precursor polyunsaturated fatty acids (PUFAs), and oxylipin biosynthetic enzymes in human PD studies to explore a potential PD oxylipin‐ome signature. Founded on disrupted oxylipin and oxylipin precursor PUFA abundance, higher PUFA intake reducing PD risk and progression, and the association between cyclooxygenase (COX) inhibition and lower PD incidence, we posit that the oxylipin‐ome plays a role in PD. Oxylipin metabolism may be a novel target for PD biomarkers and disease‐modifying therapeutics.