Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons.

TLDR

Mutations in the Cu/Zn SOD1 gene linked to familial ALS reduce enzyme activity. The study aimed to test whether chronic SOD1 inhibition causes motor neuron loss in spinal cord cultures. Chronic SOD1 inhibition was achieved using antisense oligodeoxynucleotides or diethyldithiocarbamate in organotypic spinal cord cultures. Chronic SOD inhibition caused apoptotic degeneration of spinal neurons, particularly motor neurons, over weeks; glutamate transport inhibition amplified this loss, yet antioxidant N‑acetylcysteine and a non‑NMDA antagonist largely prevented toxicity, supporting that reduced SOD1 activity—potentially worsened by impaired glutamate transport—contributes to motor neuron death in familial ALS.

Abstract

Mutations in the gene for Cu/Zn superoxide dismutase (SOD1) have been detected in some families with an autosomal dominant form of amyotrophic lateral sclerosis; these mutations appear to reduce the activity of this enzyme. To determine whether decreased SOD activity could contribute to motor neuron loss, SOD1 was inhibited chronically with either antisense oligodeoxynucleotides or diethyldithiocarbamate in spinal cord organotypic cultures. Chronic inhibition of SOD resulted in the apoptotic degeneration of spinal neurons, including motor neurons, over several weeks. Motor neuron loss was markedly potentiated by the inhibition of glutamate transport. In this paradigm, motor neuron toxicity could be entirely prevented by the antioxidant N-acetylcysteine and, to a lesser extent, by the non-N-methyl-D-aspartate glutamate receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride. 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 transport.