Reply to 'Is ALS caused by an altered oxidative activity of mutant superoxide dismutase?'

Abstract

Although the molecular mechanisms whereby mutant SOD1 causes selective motor neuron death remain unclear, a prevalent hypothesis1, 2 is that the toxic property of mutant SOD1 might be related to mutation-induced conformational changes in SOD1 that result in aberrant oxidative activities, which are catalyzed by the copper atom that is bound in the active site of mutant SOD1. The realization that the copper chaperone for SOD1 (CCS) is necessary for efficient copper incorporation into SOD1 in yeast12 and in mammals8 encouraged us to directly test this copper theory in vivo by deleting the CCS in multiple lines of mutant SOD1 mice. The absence of CCS results in a significant reduction in the level of copper-loaded mutant SOD1, but it has no effect on the onset, progression or pathology of motor neuron disease in mutant SOD1 mice7. These results demonstrate that aberrant, Cu-dependent activity of mutant SOD1 does not participate in the pathogenesis of familial ALS (FALS).