Kimura Atsuko, Namekata Kazuhiko, Guo Xiaoli, Harada Chikako, Harada Takayuki
Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Histol Histopathol. 2017 Mar;32(3):215-221. doi: 10.14670/HH-11-820. Epub 2016 Sep 9.
Glaucoma is a neurodegenerative disease of the eye and it is one of the major causes of blindness. Glaucoma is usually associated with elevated intraocular pressure (IOP) and the current therapy focuses on reduction of IOP. However, neuroprotective strategies could also be beneficial for treatment of glaucoma because the pathology of the disease involves retinal ganglion cell (RGC) death and damage to the optic nerve. Dedicator of cytokinesis 3 (Dock3) is an atypical guanine exchange factor (GEF) that belongs to a family of Dock proteins, Dock1-11. Dock3 exerts neuroprotective effects on the retina and optic nerve, and studies revealed that some of the Dock3-mediated effects are GEF-independent. One of these mechanisms is that Dock3 directly binds to the GluN2B subunit of the N-methyl-D-aspartate (NMDA) receptor. Upon stimulation by NMDA or optic nerve crush, overexpression of Dock3 promotes internalization and degradation of the NMDA receptor in the retina in vivo. It is suggested that this process is mediated by inhibition of Fyn, a Src family tyrosine kinase. Reduction in NMDA receptor expression results in decreased excitotoxic damage and oxidative stress, thereby promoting RGC survival. In this review, we discuss the therapeutic potential of neuroprotection for glaucoma and the effects of Dock3 on NMDA receptors. We also discuss apoptosis signal-regulating kinase 1 (ASK1), a member of mitogen-activated protein kinase kinase kinase that is a key regulator of cellular responses to oxidative stress, as an innovative therapeutic target for glaucoma.
青光眼是一种眼部神经退行性疾病，是导致失明的主要原因之一。青光眼通常与眼内压（IOP）升高有关，目前的治疗重点是降低眼内压。然而，神经保护策略对青光眼的治疗也可能有益，因为该疾病的病理过程涉及视网膜神经节细胞（RGC）死亡和视神经损伤。胞质分裂 dedicator 3（Dock3）是一种非典型鸟嘌呤交换因子（GEF），属于 Dock 蛋白家族（Dock1 - 11）。Dock3 对视网膜和视神经具有神经保护作用，研究表明，Dock3 介导的一些效应不依赖于 GEF。其中一种机制是，Dock3 直接与 N - 甲基 - D - 天冬氨酸（NMDA）受体的 GluN2B 亚基结合。在 NMDA 刺激或视神经挤压后，Dock3 的过表达促进体内视网膜中 NMDA 受体的内化和降解。据推测，这个过程是由Src 家族酪氨酸激酶 Fyn 的抑制介导的。NMDA 受体表达的减少导致兴奋性毒性损伤和氧化应激降低，从而促进 RGC 的存活。在这篇综述中，我们讨论了神经保护对青光眼的治疗潜力以及 Dock3 对 NMDA 受体的影响。我们还讨论了凋亡信号调节激酶 1（ASK1），它是丝裂原活化蛋白激酶激酶激酶家族的成员，是细胞对氧化应激反应的关键调节因子，作为青光眼的一个创新治疗靶点。
