Axonal Dysfunction Precedes Motor Neuronal Death in Amyotrophic Lateral Sclerosis.
Axonal Dysfunction Precedes Motor Neuronal Death in Amyotrophic Lateral Sclerosis.
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DOI：
10.1371/journal.pone.0158596
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Kuwabara S
中科院分区：
文献类型：
--
作者：
Iwai Y;Shibuya K;Misawa S;Sekiguchi Y;Watanabe K;Amino H;Kuwabara S
广泛性肌束震颤是肌萎缩侧索硬化症（ALS）的特征，提示运动轴索过度兴奋。先前的兴奋性研究表明，ALS患者的运动轴突中的持续性钠离子传导增加和钾电流减少，这两种变化均诱导过度兴奋。改变轴突兴奋性可能有助于运动神经元死亡的ALS，但运动神经元死亡的程度和异常兴奋性的关系尚未完全阐明。我们对140例ALS患者的腕部正中神经进行了多项神经兴奋性测量，并分析了复合肌肉动作电位（CMAP）振幅（运动神经元损失的指标）与兴奋性指标（如强度-持续时间常数、阈值电紧张、恢复周期和电流-阈值关系）的关系。与年龄匹配的正常对照组（n = 44）相比，ALS患者（n = 140）具有更长的强度持续时间常数（SDTC：结持续钠电流的测量; p < 0.05），去极化阈值电紧张性阈值变化较大，（p < 0.05）与去极化电流阈值关系（即调节较少;（p < 0.05），超兴奋性较大（快钾电流的测量; p < 0.05）和降低的晚期亚兴奋性（慢钾电流的量度; p < 0.05），表明持续钠电流增加和钾电流减少。在CMAP正常（> 5 mV）的患者亚组中也发现钾电流降低。回归分析显示，SDTC（R = -0.22）和去极化阈值电紧张（R = -0.22）随CMAP下降而增加。这些发现表明，运动神经过度兴奋发生在疾病的早期阶段，并在ALS运动神经元损失之前。调节改变的离子通道功能可能是ALS的一种治疗选择。
Wide-spread fasciculations are a characteristic feature in amyotrophic lateral sclerosis (ALS), suggesting motor axonal hyperexcitability. Previous excitability studies have shown increased nodal persistent sodium conductances and decreased potassium currents in motor axons of ALS patients, both of the changes inducing hyperexcitability. Altered axonal excitability potentially contributes to motor neuron death in ALS, but the relationship of the extent of motor neuronal death and abnormal excitability has not been fully elucidated. We performed multiple nerve excitability measurements in the median nerve at the wrist of 140 ALS patients and analyzed the relationship of compound muscle action potential (CMAP) amplitude (index of motor neuronal loss) and excitability indices, such as strength-duration time constant, threshold electrotonus, recovery cycle and current-threshold relationships. Compared to age-matched normal controls (n = 44), ALS patients (n = 140) had longer strength-duration time constant (SDTC: a measure of nodal persistent sodium current; p < 0.05), greater threshold changes in depolarizing threshold electrotonus (p < 0.05) and depolarizing current threshold relationship (i.e. less accommodation; (p < 0.05), greater superexcitability (a measure of fast potassium current; p < 0.05) and reduced late subexcitability (a measure of slow potassium current; p < 0.05), suggesting increased persistent sodium currents and decreased potassium currents. The reduced potassium currents were found even in the patient subgroups with normal CMAP (> 5mV). Regression analyses showed that SDTC (R = -0.22) and depolarizing threshold electrotonus (R = -0.22) increased with CMAP decline. These findings suggest that motor nerve hyperexcitability occurs in the early stage of the disease, and precedes motor neuronal loss in ALS. Modulation of altered ion channel function could be a treatment option for ALS.