Department of Biochemistry, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
Department of Stress Protein Processing, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
Neuroscience. 2018 Apr 1;375:34-48. doi: 10.1016/j.neuroscience.2018.02.003. Epub 2018 Feb 10.
Adult mammalian peripheral neurons have an intrinsic regrowth capacity in response to axonal injury. The induction of calcium ion (Ca) 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 Ca homeostasis. Although these characteristics implicate the relevance among injury-induced Ca 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 Ca release from the axonal ER was accelerated in response to injury. Additionally, axonal injury-dependent Ca 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 Ca 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.
成年哺乳动物周围神经元在受到轴突损伤后具有内在的再生能力。在损伤部位诱导钙离子（Ca）振荡对于调节再生反应至关重要。在极化神经元中，远端轴突段含有一个发育良好的内质网（ER）网络，负责 Ca 稳态。尽管这些特征暗示了损伤诱导的 Ca 动力学、轴突 ER 衍生信号与沿轴突传播的再生反应之间的相关性，但细节尚不完全清楚。在本研究中，我们发现损伤后 ER 从轴突中释放 Ca 的速度加快。此外，轴突损伤依赖性 ER 钙释放激活了损伤部位的未折叠蛋白反应（UPR）信号。轴突 UPR 信号的抑制导致轴突 ER 的碎片化和生长锥形成的破坏，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了再生。我们的研究表明，损伤诱导的 ER 中 Ca 释放引起的局部激活轴突 UPR 信号对于再生至关重要。这些发现为远距离损伤诱导信号与细胞器和细胞骨架形成的调节之间的联系提供了一个新概念，在轴突再生的协调中起着重要作用。
