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Abstract #27208 Published in IGR 12-4
Dock3 protects retinal neurones from glutamate neurotoxicity and oxidative stress
Kimura A; Namekata K; Tanaka K; Harada TNeuroscience Research 2010; 68
Dock3 is a member of Dock family proteins known as atypical Rho-guanine nucleotide exchange factors. It is exclusively expressed in the central nervous system and potentiates axonal outgrowth. Herein, we investigated the protective role of Dock3 against NMDA- and oxidative stress-induced retinal ganglion cell (RGC) death, and in an animal model of glaucoma in vivo. Transgenic mice overexpressing Dock3 (Dock3 Tg) were generated that had particularly high expression of the transgene in the retina. Following intravitreal administration of NMDA (2 nmol), the number of RGCs in wildtype (WT) mice continuously declined over the time course (3, 5, 7, 14 and 28 days after NMDA insult). However, in Dock3 Tg mice, NMDA-induced RGC death was reduced, suggesting that Dock3 plays a protective role in NMDA-mediated excitotoxicity. In addition, we have examined a role for Dock3 under oxidative stress in vitro. Dock3 overexpression reduced hydrogen peroxide-induced RGC death, indicating that Dock3 protects RGCs from oxidative stress. In order to elucidate further the protective role of Dock3, we have generated transgenic mice with deleted GLAST (glutamate/aspartate transporter) gene and Dock3 Tg (GLAST/Dock3 mice). Previous work from this laboratory revealed GLAST-deficient mice, an animal model of normal tension glaucoma, exhibit reduced number of RGCs compared withWTmice. However, the survival rate of RGCs in GLAST/Dock3 mice was increased compared with GLAST-deficient mice, indicating that Dock3 has rescued RGCs from excitotoxicity and/or oxidative stress that occur in GLAST-deficient mice. Our results suggest that Dock3 plays a vital role in protection and rescue of retinal neurones following glutamate neurotoxicity or oxidative stress. We propose Dock3 as a potential therapeutic target for neurodegenerative diseases such as glaucoma.
A. Kimura. Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, Japan.
Classification:
11.8 Neuroprotection (Part of: 11 Medical treatment)
5.1 Rodent (Part of: 5 Experimental glaucoma; animal models)
3.6 Cellular biology (Part of: 3 Laboratory methods)