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Regulation of mRNA following brain ischemia and reperfusion

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There is growing appreciation that mRNA regulation plays important roles in disease and injury. mRNA regulation and ribonomics occur in brain ischemia and reperfusion (I/R) following stroke and cardiac arrest and resuscitation. It was recognized over 40 years ago that translation arrest (TA) accompanies brain I/R and is now recognized as part of the intrinsic stress responses triggered in neurons. However, neuron death correlates to a prolonged TA in cells fated to undergo delayed neuronal death (DND). Dysfunction of mRNA regulatory processes in cells fated to DND prevents them from translating stress‐induced mRNAs such as heat shock proteins. The morphological and biochemical studies of mRNA regulation in postischemic neurons are discussed in the context of the large variety of molecular damage induced by ischemic injury. Open issues and areas of future investigation are highlighted. A sober look at the molecular complexity of ischemia‐induced neuronal injury suggests that a network framework will assist in making sense of this complexity. The ribonomic network sits between the gene network and the various protein and metabolic networks. Thus, targeting the ribonomic network may prove more effective at neuroprotection than targeting specific molecular pathways, for which all efforts have failed to the present time to stop DND in stroke and after cardiac arrest. WIREs RNA 2017, 8:e1415. doi: 10.1002/wrna.1415 This article is categorized under: RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA Evolution and Genomics > Ribonomics RNA in Disease and Development > RNA in Disease
Illustration of delayed neuronal death in hippocampal CA1 pyramidal neurons after 10‐min global forebrain ischemia and the indicated reperfusion times. CA3 neurons survive the insult. Toluidine blue staining as described in Ref . Scale bar at bottom right applies to all panels, 20× objective. For this and all subsequent figures, global brain ischemia is induced by two vessel occlusion + hypotension.
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(a) A two‐node mutually inhibitory Boolean network has four possible states where two are allowed and two unallowed due to the constraints imposed by the links. One node must dominate in this arrangement. Therefore, states in which both dominate (1, 1) or neither dominate (0,0) are unallowed states. (b) A schematic depicting the intracellular milieu as a nested hierarchy of networks in which higher levels dictate the lower level subnetworks. The subnetworks exert a feedback on the higher level networks. The red/green boxes over the metabolic and protein interaction networks depict some of the intracellular changes in specific pathways identified after brain ischemia and reperfusion. The red/green boxes over the ribonomic and gene networks depict the mutually antagonistic combinatorial influences operating in these networks.
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A model of how translation arrest and mRNA regulation contribute to the overall intracellular stress responses of neurons that will survive an ischemic insult.
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CA3 but not CA1 translates HSP70 at 8‐h reperfusion following 10‐min global brain ischemia. Images acquired from left hippocampus of the same rat. Double‐labeling immunofluorescence for 40S protein S6 (green) and HSP70 protein (red). S6 staining delineates neurons. Panels a and d are merged images; panels b and e are red HSP70 channels; panels c and f are green S6 channels, for CA1 and CA3 respectively. HSP70 prominently stained CA3 neurons but not CA1 neurons. Scale bar in (f) applies to all panels; 63× oil immersion objective and orthographic projections of 10‐slice z‐stacks.
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HuR colocalized with mRNA granules in CA3 but not CA1 at 1‐h reperfusion after 10‐min global brain ischemia. Double‐labeling immunofluorescence for polyadenylated mRNA [p(A); green] and HuR (red) in (a) control CA1, (e) control CA3, and after 10‐min ischemia and 1‐h reperfusion in (b) CA1 and (f) CA3. Panels (c) and (d) and (g) and (h) are p(A) and HuR channels for boxed areas in panels (b) and (f), respectively. Arrow in (b)–(d) points to an interneuron in CA1 that showed colocalization of HuR and mRNA granules. Arrow head points to a representative CA1 pyramidal neuron where HuR did not colocalize with mRNA granules. All neurons in CA3 showed HuR/mRNA granule colocalization. Scale bar in panel (h) applies to all panels; 63× oil immersion objective and orthographic projections of 10‐slice z‐stacks.
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Puromycin intraventricular injection induced mRNA granules in CA1. Double‐labeling immunofluorescence for polyadenylated mRNA [p(A); green] and HuR (red) in nonischemic control CA1. Dashed line shows discreet separation of cells containing mRNA granules (right) from those that do not (left); 63× oil immersion objective and orthographic projection of a 10‐slice z‐stack.
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S6 does not colocalize to mRNA granules. Double‐labeling immunofluorescence for polyadenylated mRNA [p(A); green] and 40S protein S6 (red) in CA3 after 10‐min ischemia and 1‐h reperfusion. Blow up of boxed area in panel (a) shown as: (b) red S6 channel and (c) green p(A) channel. Arrows point to locations of mRNA granules in pA channel that are absent in S6 channel. Scale bar in (c) also applies to (b); 63× oil immersion objective and orthographic projection of a 10‐slice z‐stack.
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Eukaryotic initiation factor 4G (eIF4G) colocalizes to mRNA granules. Double‐labeling immunofluorescence for polyadenylated mRNA [p(A); green] and eukaryotic initiation factor 4G (eIF4G; red). (a) Diffuse colocalization is present in sham‐operated control CA1. Granules of mRNA form in CA1 (panels b and c) and CA3 (panels d–f) after 10‐min global brain ischemia and 1‐h and 8‐h reperfusion as indicated. Panels (e) and (f) are the eIF4G and p(A) stains of the merged image in panel (d). Arrows in panels (e) and (f) point to mRNA granules that are the same in both channels. Scale bar at lower right applies to all panels; 63× oil immersion objective and orthographic projections of 10‐slice z‐stacks.
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Stress granules (SGs) increase after brain ischemia and reperfusion (I/R). Double‐labeling immunofluorescence for T‐cell internal antigen 1 (TIA‐1; green) and 40S subunit protein S6 (red) resulted in punctate yellow cytoplasmic staining of SGs. A basal level of SGs in sham‐operated CA1 controls (left) increased after 15‐min global brain ischemia and 10‐min reperfusion (right). Scale bar at bottom right applies to both panels; 63× oil immersion objective and orthographic projections of 10‐slice z‐stacks.
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RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems
RNA Evolution and Genomics > Ribonomics
RNA in Disease and Development > RNA in Disease

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