Mutant Cu,Zn superoxide dismutases and familial amyotrophic lateral sclerosis: Evaluation of oxidative hypotheses

FALS-associated missense mutations of SOD1 exhibit a toxic gain of function that leads to the death of motor neurons. The explanations for this toxicity fall into two broad categories. One involves a gain of some oxidative activity, while the second involves a gain of protein: protein interactions. Among the postulated oxidative activities are the following: (i) peroxidase action; (ii) superoxide reductase action; and, (iii) the enhancement of production of O-2(-) by partial reversal of the normal SOD activity, which then leads to increased formation of ONOO-. We will herein concentrate on evaluating the relative merits of these oxidative hypotheses and consider whether the experiments with transgenic animals that purport to disprove these oxidative explanations really do so. (C) 2003 Elsevier Inc.