Mutant SOD1 causes motor neuron disease independent of copper chaperone–mediated copper loading
NATURE NEUROSCIENCE April 2002 Volume 5 Number 4 pp 301 - 307
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 P C Wong. e-mail: 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. |
