Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOP

Abstract

Brain ischemia induces apoptosis in neuronal cells, but the mechanism is not well understood. When wild-type mice were subjected to bilateral common carotid arteries occlusion (BCCAO) for 15 min, apoptosis-associated morphological changes and appearance of TUNEL-positive cells were observed in the striatum and in the hippocampus at 48 h after occlusion. RT-PCR analysis revealed that mRNAs for ER stress-associated proapoptotic factor CHOP and an ER chaperone BiP are markedly induced at 12 h after BCCAO. Immunohistochemical analysis showed that CHOP protein is induced in nuclei of damaged neurons at 24 h after occlusion. In contrast, ischemia-associated apoptotic loss of neurons was decreased in CHOP À/À mice. Primary hippocampal neurons from CHOP À/À mice were more resistant to hypoxiareoxygenation-induced apoptosis than those from wild-type animals. These results indicate that ischemia-induced neuronal cell death is mediated by the ER stress pathway involving CHOP induction.

Roles of CHOP/GADD153 in endoplasmic reticulum stress

“…97 However, concerning the role of presenilin-1 in the ER stress pathway, the question of whether or not presenilin-1 mutations downregulate induction of BiP and CHOP is still being debated. 98,99 Therefore, it remains to be studied whether CHOP induction and ER stress-mediated apoptosis occur in the development of Alzheimer's disease. Several studies indicate that oxidative damages may have an important role in the development of Parkinson's disease.…”

ER stress and neurodegenerative diseases

“…66 It has been reported that hippocampal neurons from CHOP/Gadd153-deficient mice are more resistant to cell death induced by hypoxia-reoxygenation compared with controls. 67 Fewer neurons degenerated in the CHOPÀ/À mice after ischemia, suggesting an important role for ER stress in ischemia/stroke. In brain trauma, caspase-12 is activated as a consequence of ER stress.…”

rAAV8-733-Mediated Gene Transfer of CHIP/Stub-1 Prevents Hippocampal Neuronal Death in Experimental Brain Ischemia

“…8 However, activation of AKT by oxidative stress may facilitate cell death depending on context, 9 indicating that dynamic phosphorylation of AKT may affect several mechanisms related to cell fate. Proteostasis defects after brain ischemia are well documented, including disruption of the ubiquitin-proteasome system (UPS), 10 endoplasmic reticulum (ER) stress, 11,12 and inhibition of global protein synthesis mediated by the phosphorylation of eukaryotic initiation factor-2a (eIF2a) at serine 51 (Ser51). 13 These findings suggest that modulation of key components related to integrity of the proteome may promote neuroprotection after an ischemic insult.…”