Journal Article

ASK1 deficiency attenuates neural cell death in GLAST-deficient mice, a model of normal tension glaucoma

Harada, T, Harada, C, Ichijo, H, Namekata, K, Yoshida, H, Guo, X, Matsumoto, Y, Mitamura, Y, Tanaka, K

2010

Overview

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 Müller 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/1934 / 631/45/612/1222 / 631/45/612/1234 / 692/1807/1482 / Animals / Apoptosis / Biochemistry / Biomedical and Life Sciences / Cell Biology / Cell Cycle Analysis / Cell Death / Disease Models, Animal / Excitatory Amino Acid Transporter 1 - deficiency / Excitatory Amino Acid Transporter 1 - genetics / Glaucoma / Glutathione - metabolism / Life Sciences / Low Tension Glaucoma - metabolism / Low Tension Glaucoma - pathology / Low Tension Glaucoma - physiopathology / MAP Kinase Kinase Kinase 5 - deficiency / MAP Kinase Kinase Kinase 5 - genetics / MAP Kinase Kinase Kinase 5 - physiology / Mice / Mice, Mutant Strains / Nerve Degeneration / Neuroglia - metabolism / Neuroglia - physiology / Nitric Oxide Synthase - metabolism / Optic Nerve - physiology / original-paper / Oxidative Stress / p38 Mitogen-Activated Protein Kinases - metabolism / Retina - metabolism / Retina - physiology / Retinal Ganglion Cells - metabolism / Retinal Ganglion Cells - physiology / Retinal Neurons - metabolism / Retinal Neurons - physiology / Stem Cells / Tumor Necrosis Factor-alpha - metabolism / Vision, Ocular