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ASK1 Deficiency Attenuates Neural Cell Death in a Mouse Model of Normal Tension Glaucoma 1. Takayuki Harada¹ ¹Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan Purpose: Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase (MAPK) kinase kinase and plays an important role in stress-induced retinal ganglion cell (RGC) apoptosis (Am J Pathol. 168: 261-269, 2006). In the mouse retina, GLAST is a major glutamate transporter, and the loss of GLAST leads to optic nerve degeneration similar to normal tension glaucoma (NTG) (J Clin Invest. 117: 1763-1770, 2007). In GLAST deficient mice, the glutathione level in the retina is decreased, suggesting the involvement of oxidative stress in NTG pathogenesis. The aim of our study was to evaluate the effect of ASK1 deficiency on RGC death in GLAST deficient mice. Methods: We examined the histology and visual function of GLAST+/-:ASK1-/- and GLAST-/-:ASK1-/- mice by multifocal electroretinograms. Tumor necrosis factor (TNF)-induced activation of p38 MAPK and the production of inducible nitric oxide synthase (iNOS) in cultured Müller glial cells were examined by immunoblot analysis. TNF-induced death of cultured RGCs was quantified by counting propidium iodide-positive cells. Results & Conclusions: ASK1 deficiency protected RGCs and decreased the number of degenerating axons in the optic nerve. Consistent with these findings, visual function was significantly improved in GLAST+/-:ASK1-/- and GLAST-/-:ASK1-/- mice compared with GLAST+/- and GLAST-/- mice, respectively. TNF-induced activation of p38 MAPK and the production of iNOS were suppressed in Müller cells from ASK1-/- mice. In addition, TNF-induced cell death was also suppressed in ASK1 deficient RGCs. Thus, interrupting ASK1-dependent pathways could be beneficial for the treatment of glaucoma. |
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