Lev-Lehman E, Evron T, Broide R S, Meshorer E, Ariel I, Seidman S, Soreq H
Department of Biological Chemistry, The Life Sciences Institute, The Hebrew University of Jerusalem, Israel.
J Mol Neurosci. 2000 Feb-Apr;14(1-2):93-105. doi: 10.1385/JMN:14:1-2:093.
Environmental, congenital, and acquired immunological insults perturbing neuromuscular junction (NMJ) activity may induce a variety of debilitating neuromuscular pathologies. However, the molecular elements linking NMJ dysfunction to long-term myopathies are unknown. Here, we report dramatically elevated levels of mRNA encoding c-Fos and the "readthrough" (R) variant of acetylcholinesterase (AChE) in muscles of transgenic mice overexpressing synaptic (S) AChE in motoneurons and in control mice treated with the irreversible cholinesterase inhibitor diisopropylfluorophosphonate (DFP). Tongue muscles from DFP-treated and AChE-S transgenic mice displayed exaggerated neurite branching and disorganized, wasting fibers. Moreover, diaphragm muscles from both transgenic and DFP-treated mice exhibited NMJ proliferation. 2'-O-methyl-protected antisense oligonucleotides targeted to AChE mRNA suppressed feedback upregulation of AChE and ameliorated DFP-induced NMJ proliferation. Our findings demonstrate common transcriptional responses to cholinergic NMJ stress of diverse origin, and implicate deregulated AChE expression in excessive neurite outgrowth, uncontrolled synaptogenesis, and myopathology.
环境、先天性和后天性免疫损伤扰乱神经肌肉接头（NMJ）活动可能会诱发各种使人衰弱的神经肌肉疾病。然而，将NMJ功能障碍与长期肌病联系起来的分子机制尚不清楚。在此，我们报告在运动神经元中过表达突触型（S）乙酰胆碱酯酶（AChE）的转基因小鼠以及用不可逆胆碱酯酶抑制剂二异丙基氟磷酸酯（DFP）处理的对照小鼠的肌肉中，编码c-Fos和乙酰胆碱酯酶“通读”（R）变体的mRNA水平显著升高。DFP处理的小鼠和AChE-S转基因小鼠的舌肌显示出过度的神经突分支以及纤维紊乱和萎缩。此外，转基因小鼠和DFP处理小鼠的膈肌均表现出NMJ增殖。靶向AChE mRNA的2'-O-甲基保护反义寡核苷酸抑制了AChE的反馈上调，并改善了DFP诱导的NMJ增殖。我们的研究结果表明，对于不同来源的胆碱能NMJ应激存在共同的转录反应，并表明AChE表达失调与过度的神经突生长、不受控制的突触形成和肌病有关。
