Shaw P J, Eggett C J
Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
J Neurol. 2000 Mar;247 Suppl 1:I17-27. doi: 10.1007/BF03161151.
Current research evidence suggests that genetic factors, oxidative stress and glutamatergic toxicity, with damage to critical target proteins and organelles, may be important contributory factors to motor neuron injury in amyotrophic lateral sclerosis (ALS). Various molecular and neurochemical features of human motor neurons may render this cell group differentially vulnerable to such insults. Motor neurons are large cells with long axonal processes which lead to requirements for a high level of mitochondrial activity and a high neurofilament content compared to other neuronal groups. The lack of calcium buffering proteins parvalbumin and calbindin D28k and the low expression of the GluR2 AMPA receptor subunit may render human motor neurons particularly vulnerable to calcium toxicity following glutamate receptor activation. Motor neurons also have a high perisomatic expression of the glutamate transporter protein EAAT2 and a very high expression of the cytosolic free radical scavenging enzyme Cu/Zn superoxide dismutase (SOD1) which may render this cell group vulnerable in the face of genetic or post-translational alterations interfering with the function of these proteins. More detailed characterisation of the molecular features of human motor neurons in the future may allow the strategic development of better neuroprotective therapies for the benefit of patients afflicted by ALS.
目前的研究证据表明，遗传因素、氧化应激和谷氨酸能毒性，以及对关键靶蛋白和细胞器的损伤，可能是肌萎缩侧索硬化症（ALS）中运动神经元损伤的重要促成因素。人类运动神经元的各种分子和神经化学特征可能使该细胞群对这些损伤具有不同程度的易感性。运动神经元是具有长轴突的大细胞，与其他神经元群体相比，这导致其对线粒体活性水平和神经丝含量的要求较高。缺乏钙缓冲蛋白小白蛋白和钙结合蛋白D28k以及GluR2 AMPA受体亚基的低表达可能使人类运动神经元在谷氨酸受体激活后特别容易受到钙毒性的影响。运动神经元在胞体周围还高表达谷氨酸转运蛋白EAAT2，并且胞质自由基清除酶铜/锌超氧化物歧化酶（SOD1）的表达非常高，这可能使该细胞群在面对干扰这些蛋白质功能的遗传或翻译后改变时变得脆弱。未来对人类运动神经元分子特征进行更详细的表征，可能有助于战略性地开发更好的神经保护疗法，造福于受ALS折磨的患者。
