Irreversible Translation Arrest in the Reperfused Brain

Abstract

Irreversible translation arrest occurs in reperfused neurons that will die by delayed neuronal death. It is now recognized that suppression of protein synthesis is a general response of eukaryotic cells to exogenous stressors. Indeed, stress-induced translation arrest can be viewed as a component of cell stress responses, and consists of initiation, maintenance, and termination phases that work in concert with stress-induced transcriptional mechanisms. Within this framework, we review translation arrest in reperfused neurons. This framework provides a basis to recognize that phosphorylation of the alpha subunit of eukaryotic initiation factor 2 is the initiator of translation arrest, and a key marker indicating activation of neuronal stress responses. However, eIF2 alpha phosphorylation is reversible. Other phases of stress-induced translation arrest appear to contribute to irreversible translation arrest specifically in ischemic vulnerable neuron populations. We detail two lines of evidence supporting this view. First, ischemia, as a stress stimulus, induces irreversible co-translational protein misfolding and aggregation after 4 to 6 h of reperfusion, trapping protein synthesis machinery into functionally inactive protein aggregates. Second, ischemia and reperfusion leads to modifications of stress granules (SGs) that sequester functionally inactive 48S preinitiation complexes to maintain translation arrest. At later reperfusion durations, these mechanisms may converge such that SGs become sequestered in protein aggregates. These mechanisms result in elimination of functionally active ribosomes and preclude recovery of protein synthesis in selectively vulnerable neurons. Thus, recognizing translation arrest as a component of endogenous cellular stress response pathways will aid in making sense of the complexities of postischemic translation arrest.

Convergence of stress granules and protein aggregates in hippocampal cornu ammonis 1 at later reperfusion following global brain ischemia

“…However, the question remains if there is a relationship between SGs and PAs. Each may contribute to translation arrest in parallel, but an interaction between PAs and SGs has not been ruled out (DeGracia and Hu, 2006). Thus, we report here studies of pairwise colocalization of ubiquitin, a marker of PAs, and TIA-1 and the 40S protein S6, as markers of SGs.…”

“…Recent evidence points to the partitioning of ribosomes into translationally nonfunctional subcellular structures, including protein aggregates (PAs) and stress granules (SGs), as potential causes for the lack of recovery of normal protein synthesis in reperfused CA1 (reviewed in DeGracia and Hu, 2006).…”

The neuroprotective mechanism of brain ischemic preconditioning

“…Under electron microscopy (EM), visible protein aggregates progressively accumulate in some CA1 neurons and accumulation of the aggregates seem to occur primarily in neurons destined to undergo delayed neuronal death after brain ischemia. Further evidence [56,57] showed that the endoplasmic reticulum (ER), mitochondria and cytoplasm all respond to the accumulation of unfolded proteins by compartment-specific signaling pathways to participate in neuronal injury, whereas ubiquintin-proteasome as well as beneficial chaperones function to prevent protein aggregation and assist in protein folding [58,59] . Furthermore, by utilizing a rat transient cerebral ischemic preconditioning model, Liu et al found that ischemic preconditioning significantly reduced protein aggregation in CA1 neurons after ischemia.…”

microRNAs: Innovative Targets for Cerebral Ischemia and Stroke

“…There is thought to be a temporal window in which reversal or prevention of induction of the apoptotic cascade can occur, and such prevention of cell death would improve functional outcome [66]. Transient translational arrest is a component of the acute response to ischemia/reperfusion, which, together with the induction of the heat shock family of proteins, serves to limit the production of unfolded/misfolded proteins, thereby inhibiting the induction of pro-death pathways [67,68].…”