Role of ubiquitin carboxy terminal hydrolase-L1 in neural cell apoptosis induced by ischemic retinal injury in vivo.
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 approximately 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.
Harada
Takayuki
T
Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
Harada
Chikako
C
Wang
Yu-Lai
YL
Osaka
Hitoshi
H
Amanai
Kazuhito
K
Tanaka
Kohichi
K
Takizawa
Shuichi
S
Setsuie
Rieko
R
Sakurai
Mikako
M
Sato
Yae
Y
Noda
Mami
M
Wada
Keiji
K
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D020169:Caspases / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007511:Ischemia / Q000201:enzymology; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000201:enzymology / Q000473:pathology*; D014176:Protein Biosynthesis; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012160:Retina / Q000201:enzymology / Q000473:pathology*; D025801:Ubiquitin / Q000502:physiology; D043222:Ubiquitin Thiolesterase / Q000502:physiology*; D051636:X-Linked Inhibitor of Apoptosis Protein
D019208:Brain-Derived Neurotrophic Factor; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025801:Ubiquitin; D051636:X-Linked Inhibitor of Apoptosis Protein; D043222:Ubiquitin Thiolesterase; D020169:Caspases