Determinants of rapid disease progression in ALS

It has now been 12 years since mutations in superoxide dismutase (SOD1), an abundant, ubiquitously expressed protein, were identified^1,2 as causes of 20% of dominantly inherited ALS. The long-known involvement of this enzyme in oxidative chemistry (converting superoxide produced primarily by errors within mitochondria to hydrogen peroxide and water) fueled an initial view that selective toxicity to motor neurons resulted from loss of dismutase activity. This is not the case, however. Some mutations are fully active, whereas others are completely inactive, and no correlation has been found between retention of dismutase activity and age at disease onset or duration of disease.³ Moreover, with at least 114 different mutations now reported, there is a conspicuous absence of the simple null mutations that would decrease dismutase activity by precluding the synthesis of a full-length, or nearly full-length, mutant polypeptide. Finally, expression of ALS-linked SOD1 mutations in rodents provokes progressive motor neuron disease independent of dismutase activity,⁴ whereas total absence of SOD1 by gene deletion does not cause motor neuron disease in mice.⁵

This has led to the widely believed view that SOD1 mutant–mediated ALS arises …