Format

Send to

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

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

Author information

1
Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, Japan.

Abstract

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.

PMID:
20489729
DOI:
10.1038/cdd.2010.62
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center