Role of apoptosis signal-regulating kinase 1 in stress-induced neural cell apoptosis in vivo

Chikako Harada, Kazuaki Nakamura, Kazuhiko Namekata, Akinori Okumura, Yoshinori Mitamura, Yoko Iizuka, Kenji Kashiwagi, Kazuhiko Yoshida, Shigeaki Ohno, Atsushi Matsuzawa, Kohichi Tanaka, Hidenori Ichijo, Takayuki Harada

Research output: Contribution to journalArticlepeer-review

102 Citations (Scopus)


Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein ldnase kinase Idnase 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 ischemie 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 tlie 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.

Original languageEnglish
Pages (from-to)261-269
Number of pages9
JournalAmerican Journal of Pathology
Issue number1
Publication statusPublished - 2006 Jan


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