ABSTRACT
The discovery of mutations to the antioxidant enzyme copper, zinc superoxide dismutase (SOD) in 1993 led to still unfulfilled hopes that new treatments for amyotrophic lateral sclerosis (ALS) based on antioxidants might be forthcoming. While oxidative damage clearly occurs in degenerating tissues in ALS, a causal role of oxidation is difficult to prove (1) and in doubt by many (2,3). Several experiments from transgenic mice appear to argue strongly against copper being involved in the toxicity of mutant SOD (4,5). Many papers have now investigated the propensity of mutant SOD to aggregate when SOD is devoid of copper and zinc. Yet, there is precious little evidence that SOD aggregates are toxic and poor understanding of why they would be toxic. The available evidence is equally consistent for aggregation of SOD being protective by removing forms of SOD that are redox active. In the present review, we will re-examine the case that copper is involved in the toxicity of SOD in ALS in light of recent transgenic experiments. The hypothesis that the loss of zinc is what makes SOD initiate the death of motor neurons in both sporadic and familial ALS will be explored.
