| First Author | Harada C | Year | 2010 |
| Journal | Cell Death Differ | Volume | 17 |
| Issue | 11 | Pages | 1751-9 |
| PubMed ID | 20489729 | Mgi Jnum | J:186353 |
| Mgi Id | MGI:5432075 | Doi | 10.1038/cdd.2010.62 |
| Citation | Harada C, et al. (2010) ASK1 deficiency attenuates neural cell death in GLAST-deficient mice, a model of normal tension glaucoma. Cell Death Differ 17(11):1751-9 |
| abstractText | 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. |
