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

Cell Death Differ. 2010 Nov;17(11):1751-9. doi: 10.1038/cdd.2010.62. Epub 2010 May 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Cell Death
  • Disease Models, Animal
  • Excitatory Amino Acid Transporter 1 / deficiency*
  • Excitatory Amino Acid Transporter 1 / genetics
  • Glutathione / metabolism
  • 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
  • Oxidative Stress
  • Retina / metabolism
  • Retina / physiology
  • Retinal Ganglion Cells / metabolism
  • Retinal Ganglion Cells / physiology*
  • Retinal Neurons / metabolism
  • Retinal Neurons / physiology*
  • Tumor Necrosis Factor-alpha / metabolism
  • Vision, Ocular
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Excitatory Amino Acid Transporter 1
  • Slc1a3 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide Synthase
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • Glutathione