Nature Neuroscience5, 301 - 307 (2002)
Published online: 11 March 2002; | doi:10.1038/nn823
Mutant SOD1 causes motor neuron disease independent of copper chaperone−mediated copper loading
Jamuna R. Subramaniam1, W. Ernest Lyons1, Jian Liu2, Thomas B. Bartnikas3, Jeffrey Rothstein4, 5, Donald L. Price1, 4, 5, Don W. Cleveland2, Jonathan D. Gitlin3
& Philip C. Wong1, 5
1
Department of Pathology, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Baltimore, Maryland 21205, USA
2
Ludwig Institute of Cancer Research, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA
3
Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110, USA
4
Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
5
Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
Correspondence should be addressed to Philip C. Wong wong@jhmi.edu
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.
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