Transient Ischemia Depletes Free Ubiquitin in the Gerbil Hippocampal CA1 Neurons

Immunohistochemical techniques were employed to examine the changes in free ubiquitin within the hippocampus 1, 3, 7, 14, and 30 days after a unilateral perforant pathway lesion occurred in the rat brain. Immunoreactivity for ubiquitin was remarkably decreased in the cell body and proximal dendrites of neurons throughout the hippocampus ipsilateral to the lesion at 1 day post-lesion. At 3 days post-lesion, ubiquitin immunoreactivity was recovered in interneurons in the whole hippocampus as well as in mossy cells in the hilar region, although granule cells in the dentate gyrus and pyramidal cells in the CA1 subfield remained unlabeled, and pyramidal cells in the CA3 subfield demonstrated only weak immunoreactivity. In addition, we observed an increase in ubiquitin immunolabeling of the hilar neuropil ipsilateral to the lesion at 1 and 3 days post-lesion, and a decrease in immunolabeling in the inner portion of the molecular layer at 3 days post-lesion. All these alterations were transient, and by 7 days post-lesion, ubiquitin immunoreactivity was indistinguishable in the hippocampus ipsilateral to the lesion, compared to the controls. Immunoblot analysis also revealed a decrease in the amount of ubiquitin in the hippocampus ipsilateral to the lesion 1 and 3 days post-lesion. These data suggest that deafferentation of the perforant pathway results in transient reduction in free ubiquitin of the hippocampus, and that the ubiquitin system is involved in hippocampal plasticity following perforant lesions.

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Alterations of ubiquitin immunoreactivity in the hippocampal formation after perforant pathway lesion

Ishikawa

Iwakiri

Hidaka

et al. 2002

Acta Neuropathologica

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Postischemic Alterations of BDNF, NGF, HSP 70 and Ubiquitin Immunoreactivity in the Gerbil Hippocampus: Pharmacological Approach

et al. 2006

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1. We investigated the immunohistochemical alterations of BDNF, NGF, HSP 70 and ubiquitin in the hippocampus 1 h to 14 days after transient cerebral ischemia in gerbils. We also examined the effect of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor pitavastatin against the changes of BDNF, NGF, HSP 70 and ubiquitin in the hippocampus after cerebral ischemia in the hippocampus after ischemia. 2. The transient cerebral ischemia was carried out by clamping the carotid arteries with aneurismal clips for 5 min. 3. In the present study, the alteration of HSP 70 and ubiquitin immunoreactivity in the hippocampal CA1 sector was more pronounced than that of BDNF and NGF immunoreactivity after transient cerebral ischemia. In double-labeled immunostainings, BDNF, NGF and ubiquitin immunostaining was observed both in GFAP-positive astrocytes and MRF-1-positive microglia in the hippocampal CA1 sector after ischemia. Furthermore, prophylactic treatment with pitavastatin prevented the damage of neurons with neurotrophic factor and stress proteins in the hippocampal CA1 sector after ischemia. 4. These findings suggest that the expression of stress protein including HSP 70 and ubiquitin may play a key role in the protection against the hippocampal CA1 neuronal damage after transient cerebral ischemia in comparison with the expression of neurotrophic factor such as BDNF and NGF. The present findings also suggest that the glial BDNF, NGF and ubiquitin may play some role for helping surviving neurons after ischemia. Furthermore, our present study indicates that prophylactic treatment with pitavastatin can prevent the damage of neurons with neurotrophic factor and stress proteins in the hippocampal CA1 sector after transient cerebral ischemia. Thus our study provides further valuable information for the pathogenesis after transient cerebral ischemia.

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Protein Modifications with Ubiquitin as Response to Cerebral Ischemia-Reperfusion Injury

Hochrainer

2017

Transl. Stroke Res.

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Post-translational protein modifications present an elegant and energy efficient way to dynamically reprogram cellular protein properties and functions in response to homeostatic imbalance. One such protein modification is the tagging of proteins with the small modifier ubiquitin that can have an impact on protein stability, localization, interaction dynamics, and function. Ubiquitination is vital to any eukaryotic cell under physiological conditions, but even more important under stress including oxidative, genotoxic, and heat stress, where ubiquitination levels are drastically increased. Elevated levels of ubiquitin-protein conjugates are also observed in the brain after focal and global cerebral ischemia. Post-ischemic ubiquitination is immediately induced with reperfusion and transiently detected in neurons with survival potential located in the peri-infarct area. This review aims to critically discuss current knowledge and controversies on protein ubiquitination after cerebral ischemia, with special emphasis on potential mechanisms leading to elevated ubiquitination and on target identification. Further, possible functional implications of post-ischemic ubiquitination, including a relationship to SUMOylation, a neuroprotective modification, will be highlighted. The elevation in ubiquitinated proteins following cerebral ischemia is a greatly under-explored research area, the better understanding of which may contribute to the development of novel stroke therapies.

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Transient Ischemia Depletes Free Ubiquitin in the Gerbil Hippocampal CA1 Neurons

Cited by 11 publications

References 28 publications

Alterations of ubiquitin immunoreactivity in the hippocampal formation after perforant pathway lesion

Alterations of ubiquitin immunoreactivity in the hippocampal formation after perforant pathway lesion

Postischemic Alterations of BDNF, NGF, HSP 70 and Ubiquitin Immunoreactivity in the Gerbil Hippocampus: Pharmacological Approach

Protein Modifications with Ubiquitin as Response to Cerebral Ischemia-Reperfusion Injury

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