AXONAL ION-CHANNEL DYSFUNCTION IN AMYOTROPHIC-LATERAL-SCLEROSIS
AXONAL ION-CHANNEL DYSFUNCTION IN AMYOTROPHIC-LATERAL-SCLEROSIS
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DOI：
10.1093/brain/118.1.217
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发表时间：
1995-02-01
期刊：
影响因子：
14.5
通讯作者：
MURRAY, NMF
中科院分区：
文献类型：
--
作者：
BOSTOCK, H;SHARIEF, MK;MURRAY, NMF
在肌萎缩侧索硬化症(ALS)中，运动神经元如何或为什么死亡尚不清楚，但通过观察死亡细胞自发放电，产生肌束提供了线索。神经束可出现在运动单位的近端或远端，提示广泛的膜兴奋性障碍。为了验证这一点，我们将阈值电张力技术应用于腕部尺运动神经轴突，比较了11例ALS患者与15例正常对照组、6例良性神经束、19例下运动神经元障碍和6例上运动神经元障碍患者对100ms极化电流的反应。我们发现，与神经对照组不同，ALS患者的运动轴突对阈值下的去极化电流做出异常反应，变得比正常更多(7例)或更不兴奋(4例)。这两种类型的异常都可以在体外培养的大鼠神经中复制，也可以通过降低电压依赖的钾电导在人类运动轴突的计算机模型中复制。当足够的钾通道被阻断时，模型轴突变得不稳定并再生去极化，导致兴奋性突然下降。我们认为肌萎缩侧索硬化症的神经束是由功能性钠钾通道失衡引起的，我们认为这种离子通道功能障碍也可能是该病运动神经元变性的原因。
In amyotrophic lateral sclerosis (ALS) it is not known how or why the motor neurons die, but a clue is provided by observations that the dying cells discharge spontaneously, producing muscle fasciculations. The fasciculations can arise either proximally or distally in the motor unit, suggesting a widespread disturbance of membrane excitability. To test for this, we applied the technique of threshold electrotonus to ulnar motor axons at the wrist, comparing the responses to 100 ms polarizing currents in 11 ALS patients with those from 15 normal controls, six patients with benign fasciculations, 19 with lower motor neurons disorders and six with upper motor neuron disorders. We found that the motor axons of ALS patients, unlike those in the neurological control groups, responded abnormally to subthreshold depolarizing currents, becoming either more (seven cases) or much less excitable (four cases) than normal. Both types of abnormality could be reproduced in rat nerves in vitro, and in a computer model of human motor axons, by reducing voltage dependent potassium conductances. When sufficient potassium channels were blocked, the model axon became unstable and depolarized regeneratively, resulting in an abrupt fall in excitability. We conclude that the fasciculations in ALS are caused by an imbalance between functional sodium and potassium channels, and we propose that this ion channel dysfunction could also be responsible for the motor neuron degeneration in this disease.