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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.
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Picower Institute of MIT
The paper by Subramaniam et al. demonstrates for the first time that chaperone-mediated copper loading is not required for mutant SOD protein to produce ALS-like disease. Mutant SOD protein-mediated motor neuron disease was not affected in the absence of the SOD copper chaperone (CCS), although copper-loading was reduced by 85 percent. However, since a residual 15 percent of copper loading remains, it cannot be ruled out for certain that copper-mediated toxicity does not contribute to mutant SOD protein-mediated disease. It is formally possible that the residual CCS-independent copper loading is insufficient for normal SOD-mediated reactions, but sufficient for the aberrant oxidative chemistry implicated with the mutant SOD protein. Although overall SOD activity in spinal cord tissue was dramatically reduced, it remains to be clarified whether aberrant SOD-mediated reactions were altered.
Some small notes on the data in the paper:
(1) The number of animals for disease onset are very small in the survival table.
(2) G85R is included in the survival table, although no copper loading was detected even in the presence of CCS (figure 2b).
(3) No histology of early disease stage is shown for comparison, only late-disease stage is presented.
View all comments by Li-Huei TsaiOhio State University
Contrary to assumptions that mutant superoxide dismutase (mSOD) causes ALS via peroxynitrite-mediated oxidative injury, Subramaniam et al. provide compelling evidence that mSOD toxicity is not due to the copper-dependent catalytic activity of peroxynitrite-mediated tyrosine nitration. Although a great deal of basic research and drug discovery in ALS has been predicated on the former assumption, the work of several researchers in the last several years has cast doubt on it. Studies have indicated that neuronal nitric oxide synthase is not directly involved in ALS pathogenesis, and the lack of evidence for the efficacy of NOS inhibitors in vivo supports this view. In addition, Doroudchi et al. have demonstrated that inhibiting nitrotyrosine production and protein nitration has little effect on the lifespan of motor neurons carrying the mSOD gene. Subramaniam's article provides more concrete and elegant evidence that the toxic gain of function of mSOD is not related to its pro-oxidative capacity.
It can be argued that the small amount of altered SOD activity still present in the CCS/SOD1 mice can cause peroxynitrite formation. If the catalyst SOD is not the limiting factor in the reaction, small changes in catalyst concentration should not affect the rate of disease progression. We know that both the low- and high-copy G93A mice possess sufficient SOD activity. However, the onset of disease development is dramatically altered with levels of SOD protein. This suggests that a simple enzymatic process may not be involved in ALS pathogenesis.
This and other studies merely suggest that the modus operandi of mSOD is not peroxynitrite-induced oxidative injury: the oxidative process may still be involved in ALS pathogenesis, as oxidative stress has long been acknowledged to be a key step in neuronal death in the neurodegenerative diseases.
A number of questions pertaining to the role of SOD and mSOD in ALS remain unanswered. For example, studies indicate that prion protein (PrP) affects SOD activity, and dysregulation of PrP expression appears to alter Cu Zn-SOD activity. In addition, PrP expression is altered in mSOD mice. It remains to be seen how the two are related and how these two seemingly disparate diseases are linked.
Alternate models have been suggested to incorporate these latter questions into the story of the toxic gain of function of SOD in ALS. "Conformational disease" models that involve non-native protein structures, such as protein aggregation and high-molecular weight protein complexes, suggest that altered protein conformation may play a role in cellular toxicity. Such models are supported by the growing evidence of a pathogenic role of protein aggregates in Huntington's disease, Alzheimer's disease, alpha1-antitrypsin deficiency, and CJD. These diseases also show the involvement of the ubiquitin-proteasome system in disease pathogenesis. Future efforts to understand the properties of the SOD protein in various conformations will enable an investigation of the possible link between structural properties, enzymatic activity, and ALS pathogenesis, and will ultimately aid in drug discovery efforts in ALS.
View all comments by Tennore RameshMake a Comment
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