Reversible inactivation of superoxide-sensitive aconitase in Abeta1-42-treated neuronal cell lines.
The activity of the superoxide-sensitive enzyme aconitase was monitored to evaluate the generation of superoxide in neuronal cell lines treated with beta-amyloid (Abeta) peptide 1-42. Treatment of differentiated and undifferentiated rat PC12 and human neuroblastoma SK-N-SH cells with soluble Abeta1-42 (Abeta-derived diffusible ligands) or fibrillar Abeta1-42 caused a 35% reversible inactivation of aconitase, which preceded loss of viability and was correlated with altered cellular function. Aconitase was reactivated upon incubation of cellular extracts with iron and sulfur, suggesting that Abeta causes the release of iron from 4Fe-4S clusters. Abeta neurotoxicity was partially blocked by the iron chelator deferoxamine. These data suggest that increased superoxide generation and the release of iron from 4Fe-4S clusters are early events in Abeta1-42 neurotoxicity.
Longo
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Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, California 90089-0191, USA. vlongo@usc.edu
Viola
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Klein
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Finch
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D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051152:Clusterin; D004305:Dose-Response Relationship, Drug; D004793:Enzyme Reactivators / Q000494:pharmacology; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D007501:Iron / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology; D008024:Ligands; D046911:Macromolecular Substances; D018832:Molecular Chaperones; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D009569:Nitric Oxide / Q000096:biosynthesis; D016716:PC12 Cells; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity; D051381:Rats; D013457:Sulfur Compounds / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; C495242:CLU protein, human; D051152:Clusterin; D004793:Enzyme Reactivators; D006023:Glycoproteins; D007502:Iron Chelating Agents; D008024:Ligands; D046911:Macromolecular Substances; D018832:Molecular Chaperones; D010446:Peptide Fragments; D013457:Sulfur Compounds; C075222:amyloid beta-protein (1-42); D013481:Superoxides; D009569:Nitric Oxide; D007501:Iron; D000154:Aconitate Hydratase