SIR- Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of large motor neuron nuclei in the spinal cord. Because muscle fibres are innervated by only a single motor neuron, each loss is particularly destructive. Interneurons surrounding motor nuclei produce nitric oxide that helps modulate synaptic plasticity1 and may indirectly contribute to motor neuron destruction in ALS by Cu, Zn superoxide dismutase (SOD). Eleven unique mutations at nine distinct sites in SOD are associated with the autosomal dominant inheritance of familial ALS (see figure) 2. Because afflicted ALS patients have one normal

SOD allele, SOD activity should decrease by at most 50 per cent, which would double the steady-state concentration of superoxide. Superoxide reacts with nitric oxide at a rate of 6.7 x 109 M-1 s-1, three times faster than with native SOD, to form the powerful oxidant peroxynitrite (ONOO-) 3• Peroxynitrite in turn reacts with SOD at-105 M-1 s-1 to form a nitronium-like intermediate, which mtrates tyrosine residues4.