Abstract 2682 Lipid Changes in Niemann-Pick Type C Beyond Cholesterol

Despite decades of research, the molecular mechanisms underlying neurodegeneration remain elusive.Recent epidemiological studies have identified elevated levels of cytochrome P450 (CYP)-epoxide hydrolase (EH) polyunsaturated fatty acid (PUFA) metabolites in patients with neurodegenerative diseases, including Alzheimer's and Parkinson's diseases.While EH inhibition or genetic knockout shows neuroprotective effects in mammalian models, the complex nature of CYP-EH metabolism, which produces numerous bioactive lipid mediators, has hindered our understanding of the specific molecular mechanisms involved in neurodegeneration.To address this challenge, we established Caenorhabditis elegans (C.elegans) as a model system to dissect the role of CYP-EH metabolism in neurodegeneration.Using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), we demonstrated conservation of CYP-EH metabolism between humans and C. elegans.EH inhibition significantly reduced neurodegenerative phenotypes across multiple transgenic strains expressing pathogenic proteins associated with various neurodegenerative diseases, as assessed through phenotyping and fluorescent imaging assays.We developed a novel high-throughput platform for maintaining age-synchronized populations of day 16 adults and optimized an imaging pipeline combining spinning disk microscopy with machine learning, enabling rapid analysis of 2,000 worm neurons within two hours.This integrated approach provides a powerful tool for investigating the mechanistic links between CYP-EH metabolites and neurodegeneration, potentially revealing new therapeutic targets for neurodegenerative diseases.