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

Autor:	Sarparast M; Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States., Pourmand E; Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States., Hinman J; Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States., Vonarx D; Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States., Reason T; Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States., Zhang F; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824, United States., Paithankar S; Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, Michigan 49503, United States., Chen B; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824, United States.; Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, Michigan 49503, United States., Borhan B; Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States., Watts JL; School of Molecular Biosciences, Washington State University, Pullman, Washington 99164, United States., Alan J; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824, United States., Lee KSS; Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States.; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824, United States.
Jazyk:	angličtina
Zdroj:	ACS central science [ACS Cent Sci] 2023 Mar 16; Vol. 9 (5), pp. 870-882. Date of Electronic Publication: 2023 Mar 16 (Print Publication: 2023).
DOI:	10.1021/acscentsci.3c00052
Abstrakt:	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. Competing Interests: The authors declare no competing financial interest. (© 2023 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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