Decreased Glutamate Transport by the Brain and Spinal Cord in Amyotrophic Lateral Sclerosis


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Abstract

Background.Amyotrophic lateral sclerosis (ALS) is a chronic degenerative neurologic disorder characterized by the death of motor neurons in the cerebral cortex and spinal cord. Recent studies have suggested that the metabolism of glutamate, a potentially neurotoxic amino acid, is abnormal in patients with ALS. We hypothesized that the high-affinity glutamate transporter is the site of the defect.Methods.We measured high-affinity, sodium-dependent glutamate transport in synaptosomes from neural tissue obtained from 13 patients with ALS, 17 patients with no neurologic disease, and 27 patients with other neurodegenerative diseases (Alzheimer's disease in 15 patients and Huntington's disease in 12 patients). The groups were comparable with respect to age and the interval between death and autopsy. Synaptosomes were prepared from spinal cord, motor cortex, sensory cortex, visual cortex, striatum, and hippocampus. We also measured sodium-dependent transport of γ-aminobutyric acid and phenylalanine in the synaptosomal preparations.Results.In patients with ALS, there was a marked decrease in the maximal velocity of transport for high-affinity glutamate uptake in synaptosomes from spinal cord (-59 percent, P<0.001), motor cortex (-70 percent, P<0.001), and somatosensory cortex (-39 percent, P<0.05), but not in those from visual cortex, striatum, or hippocampus. The affinity of the transporter for glutamate was not altered. No abnormalities in glutamate transport were found in synaptosomes from patients with other chronic neurodegenerative disorders. The transport of γ-aminobutyric acid and phenylalanine was normal in patients with ALS.Conclusions.ALS is associated with a defect in high-affinity glutamate transport that has disease, region, and chemical specificity. Defects in the clearance of extracellular glutamate because of a faulty transporter could lead to neurotoxic levels of extracellular glutamate and thus be pathogenic in ALS. (N Engl J Med 1992;326: 1464–8.)AMYOTROPHIC lateral sclerosis (ALS) is a chronic progressive disease of unknown pathogenesis that is characterized by the selective degeneration of upper and lower motor neurons. It is the cause of death in 1 in 1000 people. As a result of recent reports of abnormal glutamate metabolism in ALS, we1 and others2 have postulated a role for this amino acid in the pathophysiologic process of the disease. Glutamate, the primary excitatory neurotransmitter in the brain, can exert specific neurotoxic effects through a well-described cascade of cationic and second-messenger events and can induce neuronal degeneration in vivo and in vitro.3,4 Abnormalities of …

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