Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting motor neurons of the central nervous system. Though its biology is poorly understood, one controversial theory suggests that oxidative damage is the root cause of the neuronal destruction. Support for this idea comes from studies on familial ALS which, in some cases, is due to mutation of superoxide dismutase 1 (SOD1), an enzyme that protects tissue against the oxidative effects of the oxygen free radical, superoxide. Evidence from Philip Wong's lab at Johns Hopkins University School of Medicine, Baltimore, now seems to stand that theory on its head.
Wong and coworkers took advantage of the fact that SOD1 needs the assistance of a chaperone to incorporate an essential copper atom into its active site, and they raised transgenic mice lacking the gene for this chaperone (copper chaperone for SOD1, or CCS.) Their results, which are already available from Nature Neuroscience online, were striking. Though the levels of SOD protein remained normal in CCS-negative mice, they had much lower levels of SOD1 activity than their wildtype cousins; this was true for both normal SOD and for SODs with ALS-causing mutations.
But the key observation was that the disease still progressed in CCS-negative mice, suggesting that SOD activity is not required for neurodegeneration.
So what could the role of SOD be? The authors suggest that the answer may lie in SOD-aggregates. However, convincing proponents of the oxidative theory is going to be tough. For starters, though much reduced, there is still SOD activity present in the CCS-mutant mice, so until the rate-limiting steps in the deleterious oxidative pathways are identified, it can always be argued that even a small fraction of the SOD activity is sufficient to cause the damage.—Tom Fagan
Q & A with Philip Wong-Posted 18 March 2002
Q: Could the residual SOD activity found in the CCS-negative mice be sufficient to cause the disease?
A: This is theoretically possible. However, given that the onset of disease is correlated with the amount of mutant SOD1, the significant reduction of copper incorporation into mutant SOD1 in the absence of CCS should have rescued or at least significantly ameliorated the disease if copper plays a key role. Because neither the onset nor progression of disease was altered in three different lines of mutant SOD1 mice lacking CCS, it is more reasonable to argue that CCS-dependent copper toxicity plays no role in the pathogenesis of mutant SOD1 mice.
Comment by Joan Valentine-Posted 18 March 2002
I think this is a very interesting paper that is going to influence everybody's thinking a lot, but I don't think their conclusions are absolute. It is really amazing that it seems to be more important how much of the mutant polypeptide you have, than how much the mutant polypeptide contains copper. But, they have not done the experiment where the mutant polypeptide contains no copper. One could make an argument that all you need is a little bit of copper for the protein to oxidize itself, and this would act as a nucleation site for aggregation.
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- Subramaniam JR, Lyons WE, Liu J, Bartnikas TB, Rothstein J, Price DL, Cleveland DW, Gitlin JD, Wong PC. Mutant SOD1 causes motor neuron disease independent of copper chaperone-mediated copper loading. Nat Neurosci. 2002 Apr;5(4):301-7. PubMed.