Translation arrest and ribonomics in post‐ischemic brain: layers and layers of players

Abstract

A persistent translation arrest (TA) correlates precisely with the selective vulnerability of post‐ischemic neurons. Mechanisms of post‐ischemic TA that have been assessed include ribosome biochemistry, the link between TA and stress responses, and the inactivation of translational components via sequestration in subcellular structures. Each of these approaches provides a perspective on post‐ischemic TA. Here, we develop the notion that mRNA regulation via RNA‐binding proteins, or ribonomics, also contributes to post‐ischemic TA. We describe the ribonomic network, or structures involved in mRNA regulation, including nuclear foci, polysomes, stress granules, embryonic lethal abnormal vision/Hu granules, processing bodies, exosomes, and RNA granules. Transcriptional, ribonomic, and ribosomal regulation together provide multiple layers mediating cell reprogramming. Stress gene induction via the heat‐shock response, immediate early genes, and endoplasmic reticulum stress represents significant reprogramming of post‐ischemic neurons. We present a model of post‐ischemic TA in ischemia‐resistant neurons that incorporates ribonomic considerations. In this model, selective translation of stress‐induced mRNAs contributes to translation recovery. This model provides a basis to study dysfunctional stress responses in vulnerable neurons, with a key focus on the inability of vulnerable neurons to selectively translate stress‐induced mRNAs. We suggest a ribonomic approach will shed new light on the roles of mRNA regulation in persistent TA in vulnerable post‐ischemic neurons.

Retracted

“…15,16,26,27 The selective vulnerability of neurons may be related to metabolic demands, mitochondrial sensitivity to free radical damage, or differential suppression of protein synthesis. 7,10,17,27 Increased capillary endothelial expression of CD31/PECAM is also a component of CLN.…”

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

“…This kinase phosphorylates the eIF2a (eukaryotic initiation factor 2a) thereby inhibiting the initiation step of protein synthesis (Kumar et al, 2001(Kumar et al, , 2003Hayashi et al, 2003Hayashi et al, , 2004Paschen et al, 2003;Nakka et al, 2010). However, additional mechanisms may also contribute to the inhibition of protein synthesis after transient brain ischemia (for more detailed discussion see: DeGracia and Montie, 2004;DeGracia et al, 2008). mRNAs whose translation is normally blocked by 5 0 upstream open-reading frames can still be translated in the presence of the phosphorylated form of eIF2a (eukaryotic initiation factor 2a) and this may explain the synthesis of specific proteins in UPR.…”

Towards a dynamical network view of brain ischemia and reperfusion. Part I: background and preliminaries

“…The inhibition of protein synthesis that occurs in post-ischemic neurons was initially thought of as a form of cell damage, one that reversibly goes away in cells that survive, but persists in cells that will die (White et al 2000). However, work over the past couple decades from a number of labs has now made clear that postischemic inhibition of protein synthesis is a marker of the induction of post-ischemic stress responses (Paschen 1996;Martin de la Vega et al, 2001;DeGracia et al, 2008). Importantly, we now know that the induction of post-ischemic stress responses is a clear-cut marker of the genetic reprogramming of post-ischemic brain cells .…”