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

Abstract

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 ϳ70% 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. The small 76 amino acid protein ubiquitin plays a critical role in many cellular processes, including cell cycle control, transcriptional regulation, and synaptic development.

The New Function of Two Ubiquitin C-Terminal Hydrolase Isozymes as Reciprocal Modulators of Germ Cell Apoptosis

“…With regard to cryptorchid injury, the balance between the expression of apoptosis-protecting and apoptosisinducing proteins constitutes one possible mechanism underlying the observed germ cell protection and apoptosis from apoptosis in gad and Uchl3 knockout mice, respectively. In gad mice, cryptorchid injury caused a large increase in the antiapoptotic proteins Bcl-2, Bcl-xL and XIAP, a result which was consistent with a previous report using retina [9]. In addition, the expression levels of the prosurvival proteins pCREB and BDNF also increased in gad mice.…”

Altered gene expression in cells from patients with lysosomal storage disorders suggests impairment of the ubiquitin pathway

“…Bonin et al 39 found that prosurvival protein BDNF was importantly downregulated in whole mouse brains of young GAD mice lacking UCH-L1. In contrast, Harada et al 40 showed that the levels of antiapoptotic proteins Bcl-2, XIAP and BDNF were increased in retinal cells of GAD mice reducing apoptosis. All these data suggest that the molecular responses for UCH-L1 deficiency are celltype and tissue-type specific and can result in both increased and decreased apoptosis.…”

Proteomic Analysis of Mouse Hypothalamus under Simulated Microgravity

“…The other stress-related protein that was more abundant in the hypothalamus of mice subjected to microgravity was ubiquitin carboxy-terminal hydrolase L1 (UCLH-1) (Spot 5). UCH-L1 is thought to regulate ubiquitin hydrolysis of larger ubiquitin conjugates after stress stimuli; ubiquitin in turn is thought to be a stress protein that plays an important role in protecting cells under stress conditions [18]. Peroxiredoxin (PRX) (Spot 6) is an antioxidant protein that plays a critical role in protecting against endogenously produced peroxides in both prokaryotes and eukaryotes.…”