CHRONIC INHIBITION OF SUPEROXIDE-DISMUTASE PRODUCES APOPTOTIC DEATH OF SPINAL NEURONS

Mutations in the gene for Cu/Zn superoxide dismutase (SOD1) have been detected in some families with an autosomal dominant form of amyotroph ic lateral sclerosis; these mutations appear to reduce the activity of this enzyme. To determine whether decreased SOD activity could contri bute to motor neuron loss, SOD1 was inhibited chronically with either antisense oligodeoxynucleotides or diethyldithiocarbamate in spinal co rd organotypic cultures. Chronic inhibition of SOD resulted in the apo ptotic degeneration of spinal neurons, including motor neurons, over s everal weeks. Motor neuron loss was markedly potentiated by the inhibi tion of glutamate transport. In this paradigm, motor neuron toxicity c ould be entirely prevented by the antioxidant N-acetylcysteine and, to a lesser extent, by the non-N-methyl-D-aspartate glutamate receptor a ntagonist -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochlo ride. These data support the hypothesis that the loss of motor neurons in familial amyotrophic lateral sclerosis could be due to a reduction in SOD1 activity, possibly potentiated by inefficient glutamate trans port.