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Presented By: Department of Chemistry

The role of Cytochrome P450 Metabolism of Dietary Fatty Acids on Neurodegeneration

Kin Sing Stephen Lee (Michigan State University)

Despite decades of research, the mechanism of neurodegeneration remains unclear. Ferroptosis, a non-apoptotic programmed cell death driven by an iron-dependent membrane lipid peroxidation, is an emerging target and mechanism for aging and age-associated neurodegenerative diseases. While membrane lipid peroxidation is one of the molecular hallmarks of ferroptosis, the involvement of specific polyunsaturated fatty acids and their downstream metabolites as endogenous lipid mediators of ferroptosis remains understudied. Here, we hypothesize that cytochrome P450 (CYP)-epoxide hydrolases metabolites of PUFAs are a new class of lipid mediators of ferroptosis. \r\nInvestigating the effects of specific PUFA and PUFA metabolites on ferroptosis are challenging for two main reasons. Firstly, there is a plethora of endogenous biosynthetic and metabolic enzymatic pathways, and these enzymes express differently across diverse tissues. Secondly, the mechanism of ferroptosis is not well-defined or characterized. Therefore, a system approach is likely needed. To overcome these challenges, we employed Caenorhabditis elegans (C. elegans) as a novel simplified biological model. Using a well-established neurodegenerative assay and transgenic C. elegans with green-fluorescent protein-tagged (GFP) neurons, we show that among all the tested PUFAs, only dihomo-gamma-linolenic acid (DGLA) triggers significant ferroptosis-mediated neurodegeneration after one day of exposure. Interestingly, only dopaminergic neurons and, to a lesser extent, glutaminergic neurons were affected in our studies. Using our state-of-the-art oxylipins analysis and comprehensive chemical probes, we identified the dihydroxy- metabolites of DGLA are likely the lipid mediator responsible for DGLA-induced ferroptosis-mediated neurodegeneration. We were also able to show that epoxide hydrolases play a key role in ferroptosis and neurodegeneration. \r\nIn short, our study identified a novel class of endogenous lipid mediators of ferroptosis. Our findings improve our understanding of how PUFA downstream metabolism modulates neurodegeneration. Additionally, the developed C. elegans models and identified dihydroxy- metabolites of DGLA provide a strong foundation for us to further investigate the mechanism of ferroptosis-mediated neurodegeneration that would identify a novel mechanism for ferroptosis and novel therapeutic targets for preventative or disease-altering treatments for neurodegenerative diseases. At the end of this presentation, we will also share the current drug discovery effort to target this metabolism for neurodegenerative diseases.

Kin Sing Stephen Lee (Michigan State University)

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