Dihydroxy-Metabolites of Dihomo-γ-linolenic Acid Drive Ferroptosis-Mediated Neurodegeneration

Even after decades of research, the mechanism of neurodegeneration remains understudied, hindering the discovery of effective treatments for neurodegenerative diseases. Recent reports suggest that ferroptosis could be a novel therapeutic target for neurodegenerative diseases. While polyunsaturated f...

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Published inACS central science Vol. 9; no. 5; pp. 870 - 882
Main Authors Sarparast, Morteza, Pourmand, Elham, Hinman, Jennifer, Vonarx, Derek, Reason, Tommy, Zhang, Fan, Paithankar, Shreya, Chen, Bin, Borhan, Babak, Watts, Jennifer L., Alan, Jamie, Lee, Kin Sing Stephen
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 24.05.2023
Subjects
Cell death
Cytochrome
Cytochrome P450
Cytochromes P450
Dopamine receptors
Enzymes
Epoxide hydrolase
Ferroptosis
g-linolenic acid
Investigations
Linolenic acid
Lipid peroxidation
Lipids
Metabolic pathways
Metabolites
Metabolomics
Neurodegeneration
Neurodegenerative diseases
Neurons
Polyunsaturated fatty acids
Therapeutic targets
Worms
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Summary:Even after decades of research, the mechanism of neurodegeneration remains understudied, hindering the discovery of effective treatments for neurodegenerative diseases. Recent reports suggest that ferroptosis could be a novel therapeutic target for neurodegenerative diseases. While polyunsaturated fatty acid (PUFA) plays an important role in neurodegeneration and ferroptosis, how PUFAs may trigger these processes remains largely unknown. PUFA metabolites from cytochrome P450 and epoxide hydrolase metabolic pathways may modulate neurodegeneration. Here, we test the hypothesis that specific PUFAs regulate neurodegeneration through the action of their downstream metabolites by affecting ferroptosis. We find that the PUFA dihomo-γ-linolenic acid (DGLA) specifically induces ferroptosis-mediated neurodegeneration in dopaminergic neurons. Using synthetic chemical probes, targeted metabolomics, and genetic mutants, we show that DGLA triggers neurodegeneration upon conversion to dihydroxyeicosadienoic acid through the action of CYP-EH (CYP, cytochrome P450; EH, epoxide hydrolase), representing a new class of lipid metabolites that induce neurodegeneration via ferroptosis.
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ISSN:2374-7943
2374-7951
DOI:10.1021/acscentsci.3c00052