title: Mutant SOD1 causes motor neuron disease independent of copper chaperone-mediated copper loading.
abstract: Copper-mediated oxidative damage is proposed to play a critical role in the pathogenesis of Cu/Zn superoxide dismutase (SOD1)-linked familial amyotrophic lateral sclerosis (FALS). We tested this hypothesis by ablating the gene encoding the copper chaperone for SOD1 (CCS) in a series of FALS-linked SOD1 mutant mice. Metabolic 64Cu labeling in SOD1-mutant mice lacking the CCS showed that the incorporation of copper into mutant SOD1 was significantly diminished in the absence of CCS. Motor neurons in CCS-/- mice showed increased rate of death after facial nerve axotomy, a response documented for SOD1-/- mice. Thus, CCS is necessary for the efficient incorporation of copper into SOD1 in motor neurons. Although the absence of CCS led to a significant reduction in the amount of copper-loaded mutant SOD1, however, it did not modify the onset and progression of motor neuron disease in SOD1-mutant mice. Hence, CCS-dependent copper loading of mutant SOD1 plays no role in the pathogenesis of motor neuron disease in these mouse models.
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.
authors.forename: Jamuna R
authors.initials: JR
authors.lastname: Subramaniam
authors.forename: W Ernest
authors.initials: WE
authors.lastname: Lyons
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Bartnikas
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rothstein
authors.forename: Donald L
authors.initials: DL
authors.lastname: Price
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Gitlin
authors.forename: Philip C
authors.initials: PC
authors.lastname: Wong
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D000818:Animals; D019771:Axotomy; D003300:Copper / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008017:Life Expectancy; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000378:metabolism*; D016472:Motor Neuron Disease / Q000201:enzymology* / Q000503:physiopathology; D009046:Motor Neurons / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D013116:Spinal Cord / Q000737:chemistry / Q000166:cytology / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D015996:Survival Rate; D014020:Tissue Extracts / Q000737:chemistry / Q000378:metabolism
chemical_list: C114678:CCS protein, human; C491962:Ccs protein, mouse; D018832:Molecular Chaperones; C000606290:SOD1 protein, human; D014020:Tissue Extracts; D003300:Copper; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1