Neurofilament aggregates distend a motor neuron in the spinal cord of a patient with ALS (left). A neurofilament-containing spheroidal swelling in the axon of a motor neuron from a patient with ALS (right).

Mutations in Cu/Zn superoxide dismutase 1 (SOD1) are linked to the development of familial amyotrophic lateral sclerosis (FALS), a neurodegenerative disorder that is characterized by selective motor neuron death. How do these mutations lead to the disease? One leading idea is that the mutations confer toxic properties on SOD1. Specifically, as zinc binding is lost in the mutant enzyme, the copper ion might catalyse aberrant oxidative reactions that could eventually lead to cell death.

A clear prediction of this idea is that reducing the incorporation of copper into the mutant SOD1 should lead to reduced cell death or delayed disease onset. Subramaniam et al. have now tested this hypothesis directly. They used mice that express mutant forms of SOD1, and therefore develop motor neuron disease, and ablated the gene that codes for the copper chaperone for SOD1 (CCS) to reduce copper incorporation.

The authors found that the amount of copper that was incorporated into mutant SOD1 was substantially reduced in the doubly mutant mice, a selective effect that did not seem to affect other copper-binding proteins. But despite the reduced incorporation of copper into the mutant SOD1, the development of motor neuron disease was not affected. So, the onset of cell death took place at the same time in the presence or absence of CCS, the probability of survival did not change, and the neuropathological features of the disease were similar in both groups of animals.

The factors that mediate the pathogenesis of FALS remain unknown, but the data obtained by Subramaniam et al. make a strong case against the involvement of aberrant copper-mediated oxidative reactions. This finding will allow us to switch our attention to other ideas that have been advanced to explain motor neuron death in FALS, such as other forms of oxidative damage, axonal strangulation from disorganization of neurofilaments, toxicity from intracellular aggregates, and excitotoxic death resulting from mishandling of glutamate.