Arnyotrophic lateral sclerosis (ALS) is a lethal, paralytic disorder caused by death of motor neurons in adult human brain, brainstem and spinal cord (reviewed in [1.21). The disease often begins focally and disseminates in a pattern suggesting spread among contiguous pools of motor neurons. About 10% of all ALS cases arise as a dominantly inherited trait (f&ilial ALS, FALS), which is clinically indistinguishable from sporadic ALS (SALS)[Xl. Approximately 20’%~ of FALS cases are associated with mutations in the gene encoding cytosolic Cu/Zn superoxide dismutase 1 (SODl)[4]. More than 35 mutations affecting SOD1 have been identified, specifically, in patients with FALS (summarized in [. 5]).

The SOD 1 enzyme functions as a honlodimer, with each protein consisting of 153 amino acids. It has a positively charged active channel that electrostatically attracts the superoxide anion (Oa*-) into the active site to react with copper, thereby converting(‘dismutating’) it to hydrogen peroxIde (HzO?). Normally, hydrogen peroxide exits the channel into free solution where it, in turn, is converted to water (HzO) by catalase or glutathione peroxidase [h](Fig. 1). That SOD1 thus plays a pivotal role in free radical homeostasis has prompted the hypothesis that motor neuron degeneration in FALS may be triggered by reactive oxygen species.