Axonal Activation of the Unfolded Protein Response Promotes Axonal Regeneration Following Peripheral Nerve Injury.
Axonal Activation of the Unfolded Protein Response Promotes Axonal Regeneration Following Peripheral Nerve Injury.
复制标题
未折叠蛋白反应的轴突激活促进周围神经损伤后的轴突再生。
DOI：
10.1016/j.neuroscience.2018.02.003
复制
发表时间：
2018
期刊：
影响因子：
3.3
通讯作者：
Saito A.
中科院分区：
文献类型：
--
作者：
Ohtake Y;Matsuhisa K;Kaneko M;Kanemoto S;Asada R;Imaizumi K;Saito A.
成年哺乳动物外周神经元对轴突损伤具有内在的再生能力。在损伤部位诱导钙离子（Ca2+）振荡对于再生反应的调节至关重要。在极化神经元中，远端轴突节段含有发达的内质网（ER）网络，负责Ca2+稳态。虽然这些特征暗示损伤诱导的Ca2+动力学、轴突ER衍生的信号传导和沿着轴突传播的再生反应之间的相关性，但细节尚未完全了解。在本研究中，我们发现，从轴突ER的Ca 2+释放加速响应损伤。此外，轴突损伤依赖的Ca 2+释放从ER激活未折叠蛋白反应（UPR）信号在受伤的网站。轴突UPR信号的抑制导致轴突ER的片段化和生长锥的形成中断，这表明轴突损伤后轴突UPR分支的激活通过调节ER重建和生长锥的形成促进再生。我们的研究表明，局部激活轴突UPR信号损伤诱导的Ca 2+释放的ER是至关重要的再生。这些发现提供了一个新的概念之间的联系损伤诱导的信号在一个遥远的位置和调控的细胞器和细胞骨架的形成在编排轴突再生。
Adult mammalian peripheral neurons have an intrinsic regrowth capacity in response to axonal injury. The induction of calcium ion (Ca2+) oscillations at an injured site is critical for the regulation of regenerative responses. In polarized neurons, distal axonal segments contain a well-developed endoplasmic reticulum (ER) network that is responsible for Ca2+homeostasis. Although these characteristics implicate the relevance among injury-induced Ca2+dynamics, axonal ER-derived signaling, and regenerative responses propagated along the axons, the details are not fully understood. In the present study, we found that Ca2+release from the axonal ER was accelerated in response to injury. Additionally, axonal injury-dependent Ca2+release from the ER activated unfolded protein response (UPR) signaling at injured sites. Inhibition of axonal UPR signaling led to fragmentation of the axonal ER and disrupted growth cone formation, suggesting that activation of axonal UPR branches following axonal injury promotes regeneration via regulation of ER reconstruction and formation of growth cones. Our studies revealed that local activation of axonal UPR signaling by injury-induced Ca2+release from the ER is critical for regeneration. These findings provide a new concept for the link between injury-induced signaling at a distant location and regulation of organelle and cytoskeletal formation in the orchestration of axonal regeneration.