advertisement
Abstract #25929 Published in IGR 12-2
ASK1 deficiency attenuates neural cell death in GLAST-deficient mice, a model of normal tension glaucoma
Harada C; Namekata K; Guo X; Yoshida H; Mitamura Y; Matsumoto Y; Tanaka K; Ichijo H; Harada TCell Death and Differentiation ;
See also comment(s) by Makoto Aihara •
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.
Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Tokyo, Japan
Classification:
5.1 Rodent (Part of: 5 Experimental glaucoma; animal models)
9.2.4 Normal pressure glaucoma (Part of: 9 Clinical forms of glaucomas > 9.2 Primary open angle glaucomas)
3.4.2 Gene studies (Part of: 3 Laboratory methods > 3.4 Molecular genetics)
3.6 Cellular biology (Part of: 3 Laboratory methods)
