Glaucoma, a progressive optic neuropathy due to retinal ganglion cell (RGC) degeneration, is one of the leading causes of irreversible blindness. Although glaucoma is often associated with elevated intraocular pressure (IOP), IOP elevation is not detected in a significant subset of glaucomas, such as normal tension glaucoma (NTG). Moreover, in some glaucoma patients, significant IOP reduction does not prevent progression of the disease. Thus, understanding IOP-independent mechanisms of RGC loss is important. Here, we show that mice deficient in the glutamate transporters GLAST or EAAC1 demonstrate spontaneous RGC and optic nerve degeneration without elevated IOP. In GLAST-deficient mice, the glutathione level in Müller glia was decreased; administration of glutamate receptor blocker prevented RGC loss. In EAAC1-deficient mice, RGCs were more vulnerable to oxidative stress. These findings suggest that glutamate transporters are necessary both to prevent excitotoxic retinal damage and to synthesize glutathione, a major cellular antioxidant and tripeptide of glutamate, cysteine, and glycine. We believe these mice are the first animal models of NTG that offer a powerful system for investigating mechanisms of neurodegeneration in NTG and developing therapies directed at IOP-independent mechanisms of RGC loss.
Takayuki Harada, Chikako Harada, Kazuaki Nakamura, Hun-Meng A. Quah, Akinori Okumura, Kazuhiko Namekata, Tadashiro Saeki, Makoto Aihara, Hiroshi Yoshida, Akira Mitani, Kohichi Tanaka
Title and authors | Publication | Year |
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Altered Phenotype of the Vestibular Organ in GLAST-1 Null Mice
SP Schraven, C Franz, L Rüttiger, H Löwenheim, A Lysakowski, W Stoffel, M Knipper |
Journal of the Association for Research in Otolaryngology | 2012 |
Animal Models of Glaucoma
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Dock3 stimulates axonal outgrowth via GSK-3β-mediated microtubule assembly
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The Journal of neuroscience : the official journal of the Society for Neuroscience | 2012 |
A potential neuroprotective role of apolipoprotein E-containing lipoproteins through low density lipoprotein receptor-related protein 1 in normal tension glaucoma
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The Journal of biological chemistry | 2012 |
Group I mGluR-Mediated Inhibition of Kir Channels Contributes to Retinal Muller Cell Gliosis in a Rat Chronic Ocular Hypertension Model
M Ji, Y Miao, LD Dong, J Chen, XF Mo, SX Jiang, XH Sun, XL Yang, Z Wang |
The Journal of neuroscience : the official journal of the Society for Neuroscience | 2012 |
Therapeutic targets in the ASK1-dependent stress signaling pathways
HAYAKAWA R, HAYAKAWA T, TAKEDA K, ICHIJO H |
Proceedings of the Japan Academy. Series B, Physical and biological sciences | 2012 |