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Mutant SOD1 causes motor neuron disease independent of copper chaperone–mediated copper loading

Nature Neuroscience volume 5, pages 301–307 (2002)Cite this article

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.

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Figure 1: SOD1 protein levels are not affected by the absence of CCS.
Figure 2: Reduced SOD1 activity in mutant SOD1 expressing mice lacking CCS.
Figure 3: Diminished 64Cu incorporation into the mutant SOD1 protein in the absence of CCS.
Figure 4: Increased axotomy-induced death- of motor neurons of facial nuclei in CCS−/− mice.
Figure 5: Absence of CCS does not affect the onset of motor neuron disease or lifespan in G37R, G93A and G85R mutant mice.
Figure 6: Absence of CCS does not alter neuropathological abnormalities in end-stage G37R and G93A mutant SOD1 mice.

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Acknowledgements

We thank G. Cristostomo for support in histology, E. Corpus for mouse maintenance, L. Jensen for assistance in copper content determination, T. O'Halloran for apoSOD1 and D. Borchelt and V. Culotta for discussions. This work has been supported by grants from the National Institute of Health (P.C.W., D.L.P., D.W.C. and J.D.G.), Amyotrophic Lateral Sclerosis Association (P.C.W.) and The Spinal Cord Research Foundation (J.L.).

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Authors and Affiliations

  1. Department of Pathology, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Baltimore, 21205, Maryland, USA

    Jamuna R. Subramaniam, W. Ernest Lyons, Donald L. Price & Philip C. Wong

  2. Ludwig Institute of Cancer Research, University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093, California, USA

    Jian Liu & Don W. Cleveland

  3. Department of Pediatrics, Washington University School of Medicine, St Louis, 63110, Missouri, USA

    Thomas B. Bartnikas & Jonathan D. Gitlin

  4. Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Jeffrey Rothstein & Donald L. Price

  5. Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Jeffrey Rothstein, Donald L. Price & Philip C. Wong

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  1. Jamuna R. Subramaniam
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Correspondence to Philip C. Wong.

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Subramaniam, J., Lyons, W., Liu, J. et al. Mutant SOD1 causes motor neuron disease independent of copper chaperone–mediated copper loading. Nat Neurosci 5, 301–307 (2002). https://doi.org/10.1038/nn823

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