Mutant SOD1 causes motor neuron disease independent of copper chaperone-mediated copper loading - PubMed (original) (raw)
Mutant SOD1 causes motor neuron disease independent of copper chaperone-mediated copper loading
Jamuna R Subramaniam et al. Nat Neurosci. 2002 Apr.
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.
Comment in
- A proposed mechanism of ALS fails the test in vivo.
Orr HT. Orr HT. Nat Neurosci. 2002 Apr;5(4):287-8. doi: 10.1038/nn0402-287. Nat Neurosci. 2002. PMID: 11914714 No abstract available. - Is ALS caused by an altered oxidative activity of mutant superoxide dismutase?
Bush AI. Bush AI. Nat Neurosci. 2002 Oct;5(10):919; author reply 919-20. doi: 10.1038/nn1002-919a. Nat Neurosci. 2002. PMID: 12352974 No abstract available.
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