Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Cell Death Differ. 2013 Sep;20(9):1250-6. doi: 10.1038/cdd.2013.91. Epub 2013 Jul 12.
Dedicator of cytokinesis 3 (Dock3), a new member of the guanine nucleotide exchange factors for the small GTPase Rac1, promotes axon regeneration following optic nerve injury. In the present study, we found that Dock3 directly binds to the intracellular C-terminus domain of NR2B, an N-methyl-D-aspartate (NMDA) receptor subunit. In transgenic mice overexpressing Dock3 (Dock3 Tg), NR2B expression in the retina was significantly decreased and NMDA-induced retinal degeneration was ameliorated. In addition, overexpression of Dock3 protected retinal ganglion cells (RGCs) from oxidative stress. We previously reported that glutamate/aspartate transporter (GLAST) is a major glutamate transporter in the retina, and RGC degeneration due to glutamate neurotoxicity and oxidative stress is observed in GLAST-deficient (KO) mice. In GLAST KO mice, the NR2B phosphorylation rate in the retina was significantly higher compared with Dock3 Tg:GLAST KO mice. Consistently, glaucomatous retinal degeneration was significantly improved in GLAST KO:Dock3 Tg mice compared with GLAST KO mice. These results suggest that Dock3 overexpression prevents glaucomatous retinal degeneration by suppressing both NR2B-mediated glutamate neurotoxicity and oxidative stress, and identifies Dock3 signaling as a potential therapeutic target for both neuroprotection and axonal regeneration.
细胞分裂蛋白 3（Dock3）是 Rac1 小 GTP 酶鸟嘌呤核苷酸交换因子的新成员，可促进视神经损伤后的轴突再生。在本研究中，我们发现 Dock3 可直接与 NMDA 受体亚基 NR2B 的细胞内 C 末端结构域结合。在过表达 Dock3 的转基因小鼠（Dock3 Tg）中，视网膜中 NR2B 的表达显著降低，NMDA 诱导的视网膜变性得到改善。此外，过表达 Dock3 可保护视网膜神经节细胞（RGC）免受氧化应激。我们之前报道过，谷氨酸/天冬氨酸转运体（GLAST）是视网膜中的主要谷氨酸转运体，谷氨酸神经毒性和氧化应激导致的 RGC 变性在 GLAST 缺失（KO）小鼠中观察到。在 GLAST KO 小鼠中，与 Dock3 Tg：GLAST KO 小鼠相比，视网膜中 NR2B 的磷酸化率显著升高。一致的是，与 GLAST KO 小鼠相比，GLAST KO：Dock3 Tg 小鼠的青光眼性视网膜变性得到显著改善。这些结果表明，通过抑制 NR2B 介导的谷氨酸神经毒性和氧化应激，过表达 Dock3 可预防青光眼性视网膜变性，并将 Dock3 信号确定为神经保护和轴突再生的潜在治疗靶点。
