Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taiwan.
Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan.
Elife. 2019 Jul 30;8:e49175. doi: 10.7554/eLife.49175.
NogoA inhibits neurite outgrowth of motoneurons (NOM) through interaction with its receptors, Nogo66/NgR. Inhibition of Nogo receptors rescues NOM, but not to the extent exhibited by -knockout mice, suggesting the presence of other pathways. We found that NogoA-overexpressing muscle cells reduced phosphoglycerate kinase 1 (Pgk1) secretion, resulting in inhibiting NOM. Apart from its glycolytic role and independent of the Nogo66 pathway, extracellular Pgk1 stimulated NOM by triggering a reduction of p-Cofilin-S3, a growth cone collapse marker, through decreasing a novel Rac1-GTP/p-Pak1-T423/p-P38-T180/p-MK2-T334/p-Limk1-S323/p-Cofilin-S3 molecular pathway. Not only did supplementary Pgk1 enhance NOM in defective cells, but injection of Pgk1 rescued denervation in muscle-specific NogoA-overexpression of zebrafish and an Amyotrophic Lateral Sclerosis mouse model, SOD1 G93A. Thus, Pgk1 secreted from muscle is detrimental to motoneuron neurite outgrowth and maintenance.
NogoA 通过与其受体 Nogo66/NgR 相互作用抑制运动神经元（NOM）的轴突生长。抑制 Nogo 受体可挽救 NOM，但不能达到 -knockout 小鼠所表现出的程度，这表明存在其他途径。我们发现，过表达 NogoA 的肌肉细胞减少了磷酸甘油酸激酶 1（Pgk1）的分泌，从而抑制了 NOM。除了其糖酵解作用和独立于 Nogo66 途径之外，细胞外 Pgk1 通过触发生长锥塌陷标志物 p-Cofilin-S3 的减少，刺激 NOM，其机制是通过降低一种新的 Rac1-GTP/p-Pak1-T423/p-P38-T180/p-MK2-T334/p-Limk1-S323/p-Cofilin-S3 分子途径。补充 Pgk1 不仅增强了有缺陷细胞中的 NOM，而且在肌肉特异性 NogoA 过表达的斑马鱼和肌萎缩侧索硬化症（SOD1 G93A）小鼠模型中，Pgk1 的注射也挽救了运动神经元的去神经支配。因此，肌肉分泌的 Pgk1 不利于运动神经元轴突生长和维持。
