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(American Journal of Pathology. 2004;164:59-64.)
© 2004 American Society for Investigative Pathology

Role of Ubiquitin Carboxy Terminal Hydrolase-L1 in Neural Cell Apoptosis Induced by Ischemic Retinal Injury in Vivo

Takayuki Harada^*, Chikako Harada^*, Yu-Lai Wang^*, Hitoshi Osaka^*, Kazuhito Amanai, Kohichi Tanaka, Shuichi Takizawa^*, Rieko Setsuie^*, Mikako Sakurai^*, Yae Sato^*, Mami Noda and Keiji Wada^*

From the Department of Degenerative Neurological Diseases,^* National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo; Laboratory of Molecular Neuroscience, School of Biomedical Science and Medical Research Institute, Tokyo Medical and Dental University, Tokyo; Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Corporation (JST), Kawaguchi, Saitama; Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan

Ubiquitin is thought to be a stress protein that plays an important role in protecting cells under stress conditions; however, its precise role is unclear. Ubiquitin expression level is controlled by the balance of ubiquitinating and deubiquitinating enzymes. To investigate the function of deubiquitinating enzymes on ischemia-induced neural cell apoptosis in vivo, we analyzed gracile axonal dystrophy (gad) mice with an exon deletion for ubiquitin carboxy terminal hydrolase-L1 (UCH-L1), a neuron-specific deubiquitinating enzyme. In wild-type mouse retina, light stimuli and ischemic retinal injury induced strong ubiquitin expression in the inner retina, and its expression pattern was similar to that of UCH-L1. On the other hand, gad mice showed reduced ubiquitin induction after light stimuli and ischemia, whereas expression levels of antiapoptotic (Bcl-2 and XIAP) and prosurvival (brain-derived neurotrophic factor) proteins that are normally degraded by an ubiquitin-proteasome pathway were significantly higher. Consistently, ischemia-induced caspase activity and neural cell apoptosis were suppressed 70% in gad mice. These results demonstrate that UCH-L1 is involved in ubiquitin expression after stress stimuli, but excessive ubiquitin induction following ischemic injury may rather lead to neural cell apoptosis in vivo.

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