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From the Department of Molecular Neurobiology,* Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo; the Laboratory of Molecular Neuroscience, School of Biomedical Science and Medical Research Institute, Tokyo Medical and Dental University, Tokyo; the Department of Ophthalmology, School of Medicine, Sapporo Medical University, Sapporo; the Department of Ophthalmology, University of Yamanashi Faculty of Medicine, Yamanashi; the Department of Ophthalmology and Visual Sciences, ¶ Hokkaido University Graduate School of Medicine, Sapporo; the Laboratory of Cell Signaling,|| Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo; Core Research for Evolutional Science and Technology,** Japan Science and Technology Corporation, Tokyo; Strategic Approach to Drug Discovery and Development in Pharmaceutical Sciences, Center of Excellence Program, Tokyo; and Precursory Research for Embryonic Science and Technology, Japan Science and Technology Corporation, Kawaguchi, Japan
Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays an important role in oxidative stress-induced apoptosis. In the present study, we used ASK1 knockout (KO) mice to examine the possibility that ASK1 is involved in the neural cell apoptosis that occurs during retinal development and ischemic injury. ASK1 was expressed in retinal neurons, including retinal ganglion cells (RGCs), but retinal structure and extent of cell death during development were normal in ASK1 KO mice. On the other hand, the strain was less susceptible to ischemic injury, and the number of surviving retinal neurons was significantly increased compared with that in wild-type mice. Interestingly, ischemia-induced phosphorylation of p38 mitogen-activated protein kinase (p38), which mediates RGC apoptosis, was almost completely suppressed in ASK1 KO mice. In such retinas, the numbers of cleaved caspase-3- and TUNEL-positive neurons were apparently decreased compared with those in wild-type mice. Furthermore, cultured RGCs from ASK1 KO mice were resistant to H2O2-induced apoptosis. Our findings suggest that ASK1 is involved in the neural cell apoptosis after various kinds of oxidative stress. Thus, inhibition of the ASK1-p38 pathway could be useful for the treatment of neurodegenerative diseases including glaucoma.
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