The potential role of glutamate transporters in the pathogenesis of normal tension glaucoma.
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.
Harada
Takayuki
T
Laboratory of Molecular Neuroscience, School of Biomedical Science and Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Harada
Chikako
C
Nakamura
Kazuaki
K
Quah
Hun-Meng A
HM
Okumura
Akinori
A
Namekata
Kazuhiko
K
Saeki
Tadashiro
T
Aihara
Makoto
M
Yoshida
Hiroshi
H
Mitani
Akira
A
Tanaka
Kohichi
K
D027322:Amino Acid Transport System X-AG / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005901:Glaucoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018698:Glutamic Acid / Q000633:toxicity; D007429:Intraocular Pressure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009901:Optic Nerve Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D012165:Retinal Ganglion Cells / Q000378:metabolism; D014785:Vision, Ocular
D027322:Amino Acid Transport System X-AG; D018698:Glutamic Acid