Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 97, Issue 6, Pages 2886-2891Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.040461197
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Funding
- NIDDK NIH HHS [DK44464, R01 DK044464, R37 DK044464] Funding Source: Medline
- NIGMS NIH HHS [R37 GM050016, R01 GM050016] Funding Source: Medline
- NINDS NIH HHS [NS37771, NS37145] Funding Source: Medline
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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 (CU)-C-64 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.
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