Engelhardt J I, Siklos L, Appel S H
Department of Neurology and Psychiatry, Albert Szent-Gyorgyi Medical University, Szeged, Hungary.
J Neuropathol Exp Neurol. 1997 Jan;56(1):21-39. doi: 10.1097/00005072-199701000-00003.
Calcium homeostasis and ultrastructure are altered in motor axon terminals (AT) of amyotrophic lateral sclerosis (ALS) patients and in mice injected with ALS IgG and exhibit increased density of synaptic vesicles and increased intracellular calcium. To develop an immune-mediated passive transfer experimental model of both systemic weakness and altered morphology, mice were inoculated intraperitoneally with anti-motoneuronal IgG. Animals initially manifested muscle stiffness and evidence of autonomic cholinergic hyperactivity. Electron microscopic cytochemistry within 12 hours (h) demonstrated significantly increased density of synaptic vesicles and calcium both in axon terminals of neuromuscular junctions and synaptic boutons on spinal motoneurons. After 24 h the mice were severely weak and premorbid. The number of synaptic vesicles was still larger than normal, but calcium was depleted from axon terminals and synaptic boutons. The motoneuron perikarya demonstrated the dilatation of the Golgi system and the rough endoplasmic reticulum with an increased amount of calcium. The NMDA receptor antagonist, MK-801, and the L-type calcium channel antagonist, Diltiazem, prevented clinical symptoms and some morphological alterations. These data demonstrate that high titer anti-motoneuronal IgG can induce severe weakness and produce similar ultrastructural features of motor axon terminals in human ALS and in mice injected with ALS IgG, and support a key role for calcium in selective vulnerability of motoneurons.
肌萎缩侧索硬化症（ALS）患者以及注射了ALS免疫球蛋白G（IgG）的小鼠的运动轴突终末（AT）中的钙稳态和超微结构发生改变，表现为突触小泡密度增加和细胞内钙含量增加。为了建立一个系统性肌无力和形态改变的免疫介导被动转移实验模型，给小鼠腹腔注射抗运动神经元IgG。动物最初表现出肌肉僵硬和自主胆碱能功能亢进的迹象。12小时内的电子显微镜细胞化学显示，神经肌肉接头的轴突终末和脊髓运动神经元上的突触小体中的突触小泡和钙的密度均显著增加。24小时后，小鼠严重虚弱且处于发病前状态。突触小泡的数量仍高于正常水平，但轴突终末和突触小体中的钙已耗尽。运动神经元胞体显示高尔基体系统和粗面内质网扩张，钙含量增加。NMDA受体拮抗剂MK-801和L型钙通道拮抗剂地尔硫卓可预防临床症状和一些形态学改变。这些数据表明，高滴度的抗运动神经元IgG可诱发严重肌无力，并在人类ALS和注射了ALS IgG的小鼠中产生与运动轴突终末相似的超微结构特征，支持钙在运动神经元选择性易损性中起关键作用。
