Copper chaperone for superoxide dismutase is essential to activate mammalian Cu/Zn superoxide dismutase

Philip C. Wong, Darrel Waggoner, Jamuna R. Subramaniam, Lino Tessarollo, Thomas B. Bartnikas, Valeria C. Culotta, Donald L Price, Jeffrey Rothstein, Jonathan D. Gitlin

Research output: Contribution to journalArticlepeer-review


Recent studies in Saccharomyces cerevisiae suggest that the delivery of copper to Cu/Zn superoxide dismutase (SOD1) is mediated by a cytosolic protein termed the copper chaperone for superoxide dismutase (CCS). To determine the role of CCS in mammalian copper homeostasis, we generated mice with targeted disruption of CCS alleles (CCS(-/-) mice). Although CCS(-/-) mice are viable and possess normal levels of SOD1 protein, they reveal marked reductions in SOD1 activity when compared with control littermates. Metabolic labeling with 64Cu demonstrated that the reduction of SOD1 activity in CCS(-/-) mice is the direct result of impaired Cu incorporation into SOD1 and that this effect was specific because no abnormalities were observed in Cu uptake, distribution, or incorporation into other cuproenzymes. Consistent with this loss of SOD1 activity, CCS(-/-) mice showed increased sensitivity to paraquat and reduced female fertility, phenotypes that are characteristic of SOD1-deficient mice. These results demonstrate the essential role of any mammalian copper chaperone and have important implications for the development of novel therapeutic strategies in familial amyotrophic lateral sclerosis.

Original languageEnglish (US)
Pages (from-to)2886-2891
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number6
StatePublished - Mar 14 2000

ASJC Scopus subject areas

  • General


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