Journal
CELL DEATH AND DIFFERENTIATION
Volume 17, Issue 11, Pages 1751-1759Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2010.62
Keywords
glaucoma; ASK1; glutamate transporter; glia; neural cell death
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Ministry of Health, Labour and Welfare of Japan
- Japan Society for the Promotion of Science for Young Scientists
- Tokyo Metropolitan Government
- Uehara Memorial Foundation
- Naito Foundation
- Suzuken Memorial Foundation
- Daiwa Securities Health Foundation
- Takeda Science Foundation
- Japan Medical Association
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Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase (MAPK) kinase kinase and has an important role in stress-induced retinal ganglion cell (RGC) apoptosis. In the mammalian retina, glutamate/ aspartate transporter (GLAST) is a major glutamate transporter, and the loss of GLAST leads to optic nerve degeneration similar to normal tension glaucoma (NTG). In GLAST(-/-) mice, the glutathione level in the retina is decreased, suggesting the involvement of oxidative stress in NTG pathogenesis. To test this hypothesis, we examined the histology and visual function of GLAST(+/-):ASK1(-/-) and GLAST(-/-) : ASK1(-/-) mice by multifocal electroretinograms. ASK1 deficiency protected RGCs and decreased the number of degenerating axons in the optic nerve. Consistent with this finding, visual function was significantly improved in GLAST(+/-):ASK1(-/-) and GLAST(-/-) : ASK1(-/-) mice compared with GLAST(+/-) and GLAST(-/-) mice, respectively. The loss of ASK1 had no effects on the production of glutathione or malondialdehyde in the retina or on the intraocular pressure. Tumor necrosis factor (TNF)-induced activation of p38 MAPK and the production of inducible nitric oxide synthase were suppressed in ASK1-deficient Muller glial cells. In addition, TNF-induced cell death was suppressed in ASK1-deficient RGCs. These results suggest that ASK1 activation is involved in NTG-like pathology in both neural and glial cells and that interrupting ASK1-dependent pathways could be beneficial in the treatment of glaucoma, including NTG. Cell Death and Differentiation (2010) 17, 1751-1759; doi:10.1038/cdd.2010.62; published online 21 May 2010
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