Visualization and regulation of ischemia-induced stress response in brain.

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An integral component of the cellular response to environmental challenge is expression, usually by de novo protein synthesis, of stress-associated polypeptides, such as heat shock proteins (induced by high temperature), glucose-regulated proteins (GRPs ; induced by glucose deprivation), and oxygen-regulated proteins (induced by oxygen deprivation). These biosynthetic responses are well preserved from prokaryotes to mammals, and have been hypothesized to contribute importantly to maintenance of cellular homeostasis as cellular adaptation to altered environmental conditions is under way.Astrocytes are strategically positioned to exert cytoprotective effects on neurons, the latter known for their vulnerability to changes in the local environment. Such neuro-protective and even neuro-trophic properties of astrocytes have been suggested in the setting of trauma, inflammation, and ischemic insults. To analyze specific mechanisms through which astrocytes mediate these effects, we analyzed po … More lypeptides made by astrocytes exposed to hypoxia, an important component of the ischemic milieu. Our studies have identified a novel 150 kDa protein, ORP150. This endoplasmic reticulum (ER)-associated chaperone has been shown to contribute importantly to the viability of several cultured cell lines under conditions of oxygen deprivation.In view of the susceptibility of neurons to ischemic stress, we hypothesized that such vulnerability might be due, at least in part, to limited expression of ORP15O.In contrast, the resistance of astrocytes to ischemic stress might result from abundant ORP150 expression.Oxygen-regulated protein 150 kDa (ORP150) is a novel endoplasmic reticulum-associated chaperone induced by oxygen deprivation/ischemia. Although ORP15O was modestly upregulated in neurons from human brain undergoing ischemic stress, there was robust induction in astrocytes. Cultured neurons overexpressing ORP150 were resistant to hypoxemic stress, whereas astrocytes with inhibited ORP15O expression were more vulnerable. Mice with targeted neuronal overexpression of ORP150 displayed smaller strokes compared with controls. Neurons with increased ORP150 demonstrated suppressed caspase-3-like activity and enhanced elaboration of neurotrophic BDNF under hypoxia. These data indicate that ORP150 is an integral participant in ischemic cytoprotective pathways. Less