DECREASED GLUTAMATE TRANSPORT BY THE BRAIN AND SPINAL-CORD IN AMYOTROPHIC-LATERAL-SCLEROSIS
DECREASED GLUTAMATE TRANSPORT BY THE BRAIN AND SPINAL-CORD IN AMYOTROPHIC-LATERAL-SCLEROSIS
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DOI：
10.1056/nejm199205283262204
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发表时间：
1992-05-28
影响因子：
158.5
通讯作者：
KUNCL, RW
中科院分区：
文献类型：
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作者：
ROTHSTEIN, JD;MARTIN, LJ;KUNCL, RW
背景。肌萎缩侧索硬化症（ALS）是一种慢性退行性神经系统疾病，其特征是大脑皮质和脊髓中的运动神经元死亡。近期研究表明，谷氨酸（一种可能具有神经毒性的氨基酸）的代谢在ALS患者中异常。我们假设高亲和力谷氨酸转运体是缺陷所在部位。
方法。我们测量了来自13例ALS患者、17例无神经系统疾病患者以及27例其他神经退行性疾病患者（15例阿尔茨海默病患者和12例亨廷顿病患者）的神经组织突触小体中的高亲和力、钠依赖性谷氨酸转运情况。这些组在年龄以及死亡和尸检之间的间隔方面具有可比性。从脊髓、运动皮质、感觉皮质、视觉皮质、纹状体和海马体中制备突触小体。我们还测量了突触小体制剂中γ - 氨基丁酸和苯丙氨酸的钠依赖性转运情况。
结果。在ALS患者中，脊髓（-59%，P < 0.001）、运动皮质（-70%，P < 0.001）和躯体感觉皮质（-39%，P < 0.05）的突触小体中高亲和力谷氨酸摄取的最大转运速度显著降低，但视觉皮质、纹状体或海马体的突触小体中没有这种情况。转运体对谷氨酸的亲和力没有改变。在其他慢性神经退行性疾病患者的突触小体中未发现谷氨酸转运异常。ALS患者中γ - 氨基丁酸和苯丙氨酸的转运是正常的。
结论。ALS与具有疾病、区域和化学特异性的高亲和力谷氨酸转运缺陷有关。由于转运体有缺陷导致细胞外谷氨酸清除障碍，可能会使细胞外谷氨酸达到神经毒性水平，从而在ALS中具有致病性。
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 gamma-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 gamma-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.