ASK1 deficiency attenuates neural cell death in GLAST-deficient mice, a model of normal tension glaucoma.
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.
Harada
C
C
Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, Japan.
Namekata
K
K
Guo
X
X
Yoshida
H
H
Mitamura
Y
Y
Matsumoto
Y
Y
Tanaka
K
K
Ichijo
H
H
Harada
T
T
D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D004195:Disease Models, Animal; D027341:Excitatory Amino Acid Transporter 1 / Q000172:deficiency* / Q000235:genetics; D005978:Glutathione / Q000378:metabolism; D057066:Low Tension Glaucoma / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D048848:MAP Kinase Kinase Kinase 5 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009410:Nerve Degeneration; D009457:Neuroglia / Q000378:metabolism / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009900:Optic Nerve / Q000502:physiology; D018384:Oxidative Stress; D012160:Retina / Q000378:metabolism / Q000502:physiology; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000502:physiology*; D055351:Retinal Neurons / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014785:Vision, Ocular; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D027341:Excitatory Amino Acid Transporter 1; C493393:Slc1a3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D005978:Glutathione