title: Copper chaperone for superoxide dismutase is essential to activate mammalian Cu/Zn superoxide dismutase.
abstract: 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 (64)Cu 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.
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. wong@jhmi.edu
authors.forename: P C
authors.initials: PC
authors.lastname: Wong
authors.forename: D
authors.initials: D
authors.lastname: Waggoner
authors.forename: J R
authors.initials: JR
authors.lastname: Subramaniam
authors.forename: L
authors.initials: L
authors.lastname: Tessarollo
authors.forename: T B
authors.initials: TB
authors.lastname: Bartnikas
authors.forename: V C
authors.initials: VC
authors.lastname: Culotta
authors.forename: D L
authors.initials: DL
authors.lastname: Price
authors.forename: J
authors.initials: J
authors.lastname: Rothstein
authors.forename: J D
authors.initials: JD
authors.lastname: Gitlin
mesh_terms: D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology; D000818:Animals; D002460:Cell Line; D003300:Copper / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000201:enzymology; D004789:Enzyme Activation; D005260:Female; D005298:Fertility / Q000235:genetics; D005347:Fibroblasts / Q000201:enzymology; D006540:Herbicides / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016296:Mutagenesis; D010269:Paraquat / Q000494:pharmacology; D011995:Recombination, Genetic; D029701:Saccharomyces cerevisiae Proteins; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013997:Time Factors; D014018:Tissue Distribution; D015032:Zinc / Q000378:metabolism*
chemical_list: C491960:CCS1 protein, S cerevisiae; C491962:Ccs protein, mouse; D006540:Herbicides; D018832:Molecular Chaperones; D029701:Saccharomyces cerevisiae Proteins; D003300:Copper; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D015032:Zinc; D010269:Paraquat