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

Recent studies in Saccharomyces cerevisiae suggest that the delivery of cop per to Cu/Zn superoxide dismutase (SOD1) is mediated by a cytosolic protein termed the copper chaperone for superoxide dismutase (CCS). To determine t he role of CCS in mammalian copper homeostasis, we generated mice with targ eted disruption of CCS alleles (CCS-/- mice). Although CCS-/- mice are viab le and possess normal levels of SOD1 protein, they reveal marked reductions in SOD1 activity when compared with control littermates, Metabolic labelin g 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 uptak e, distribution, or incorporation into other cuproenzymes. Consistent with this loss of SOD1 activity, CCS-/- mice showed increased sensitivity to par aquat and reduced female fertility, phenotypes that are characteristic of S OD1-deficient mice. These results demonstrate the essential role of any mam malian copper chaperone and have important implications for the development of novel therapeutic strategies in familial amyotrophic lateral sclerosis.