Department of Life Science and Medical Bioscience, Waseda University, Shinjuku-ku, Tokyo, 162-8480, Japan.
Department of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
Neuromolecular Med. 2024 Sep 12;26(1):37. doi: 10.1007/s12017-024-08805-1.
As the primary connection between the eye and brain, the optic nerve plays a pivotal role in visual information transmission. Injuries to the optic nerve can occur for various reasons, including trauma, glaucoma, and neurodegenerative diseases. Retinal ganglion cells (RGCs), a type of neurons that extend axons through the optic nerve, can rapidly respond to injury and initiate cell death. Additionally, following optic nerve injury microglia, which serve as markers of neuroinflammation, transition from a resting state to an activated state. The phosphorylation of collapsin response mediator protein2 (CRMP2) in the semaphorin 3A (Sema3A) signalling pathway affects several processes, including axon guidance and neuron regeneration. In this study, we used an optic nerve crush (ONC) mouse model to investigate the effects of suppressing CRMP2 phosphorylation on microglia activation. We found that CRMP2 phosphorylation inhibitor suppressed RGCs loss and promoted neuronal regeneration following ONC. In addition, CRMP2 S522A mutant (CRMP2 KI) mice exhibited decreased microglial activation in both the retina and optic nerve following ONC. These results suggest that inhibiting the phosphorylation of CRMP2 can alleviate the loss of RGCs and microglial activation after optic nerve injury, providing insight into the development of treatments for optical neuropathies and neurodegenerative diseases.
作为眼睛和大脑之间的主要连接，视神经在视觉信息传递中起着至关重要的作用。视神经损伤的原因有很多，包括创伤、青光眼和神经退行性疾病。视网膜神经节细胞（RGCs）是一种通过视神经延伸轴突的神经元，它们可以快速对损伤做出反应并引发细胞死亡。此外，视神经损伤后，小胶质细胞（microglia）从静止状态转变为激活状态，成为神经炎症的标志物。神经丝氨酸苏氨酸激酶（CRMP）2 在信号通路中的磷酸化在几个过程中起作用，包括轴突导向和神经元再生。在这项研究中，我们使用视神经挤压（ONC）小鼠模型来研究抑制 CRMP2 磷酸化对小胶质细胞激活的影响。我们发现，CRMP2 磷酸化抑制剂抑制了 ONC 后 RGCs 的损失并促进了神经元的再生。此外，CRMP2 S522A 突变（CRMP2 KI）小鼠在 ONC 后视网膜和视神经中的小胶质细胞激活减少。这些结果表明，抑制 CRMP2 的磷酸化可以减轻视神经损伤后 RGCs 的损失和小胶质细胞的激活，为开发治疗视神经病变和神经退行性疾病的方法提供了思路。
