Dock family proteins in neurodegeneration

Dock3是小GTPase Rac1的鸟嘌呤核苷酸交换因子。我们发现Dock3直接与n -甲基- d -天冬氨酸（NMDA）受体亚基NR2B结合。在过表达Dock3 （Dock3 Tg）的转基因小鼠中，NR2B在视网膜中的表达显著降低，nmda诱导的视网膜变性得到改善。此外，Dock3的过表达保护视网膜神经节细胞（RGCs）免受氧化应激。我们之前报道了在glast缺陷（KO）小鼠中观察到谷氨酸神经毒性和氧化应激引起的RGC变性。在GLAST KO小鼠中，视网膜NR2B磷酸化率明显高于Dock3 Tg:GLAST KO小鼠。同样，与GLAST KO小鼠相比，GLAST KO:Dock3 Tg小鼠青光眼视网膜变性明显改善。这些结果表明Dock3过表达通过抑制nr2b介导的谷氨酸神经毒性和氧化应激来预防青光眼视网膜变性。

Dock3 is a guanine nucleotide exchange factors for the small GTPase Rac1. We found that Dock3 directly binds to 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 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.