Role of CuZn superoxide dismutase in familial amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a late onset neuro-degenerative disorder characterized by highly selective death of large motor neurons in the cerebral cortex and spinal cord. A proportion of the familial cases (FALS) with autosomal dominant transmission was linked to chromosome 21q and the defective gene was shown to be the Cu/Zn superoxide dismutase gene (SOD1). SOD1 is a ubiquitously expressed cytoplasmic metalloenzyme catalyzing the dismutation of the superoxide free radical into hydrogen peroxide and molecular oxygen. We have screened our FALS patients for mutations in the SOD1 gene and found mutations in about 13% of the cases. All but one mutation were single base pair substitutions resulting in amino acid changes (i.e. missense mutations) predicted to produce structurally defective molecules, and some of which significantly reduced the SOD1 enzyme activity in lymphoblasts. We have also identified a two base pairs deletion, which introduces a premature stop codon at position 131 and is predicted to result in the translation of a truncated molecule.It has been hypothesized that the pathology observed in FALS cases with SOD1 mutations is due to a gain of a new deleterious function of the mutant enzyme and not to a simple loss of dismutase activity. However the exact mechanism of SOD1 toxicity is still unknown and the specificity of the degenerating cell populations remains to be addressed. In this work, we investigated whether the damage seen in ALS with SOD1 mutations results from direct motor neuron toxicity. We have generated transgenic animals carrying a human SOD1 cDNA with the G37R mutation associated with FALS, driven by the neurofilament light chain promoter in order to specifically express the mutant protein in neuronal tissues. We show that transgenic animals express high levels of the human SOD1 protein in neuronal tissues, especially in the spinal cord where the motor neurons are concentrated, but develop no apparent motor deficit at up to 2 years of age. Our animal model suggests that neuron specific expression of mutant human SOD1 might not be sufficient for the development of the disease in mice, and hints towards the involvement of additional yet unidentified cell types/mechanisms