Chapter 12 Protein phosphorylation and the regulation of mRNA translation following cerebral ischemia

Wieloch, Tadeusz; Bergstedt, Kerstin; Hu, Bing

doi:10.1016/s0079-6123(08)63266-5

Cited by 26 publications

(8 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As previous reviews have summarized in detail studies of translation arrest after I/R (Hossmann, 1993;Wieloch et al, 1993Wieloch et al, , 1996DeGracia et al, 2002;DeGracia, 2004;Hu et al, 2004;Hu, 2006), here we will only outline the salient issues. The initial work of Kleihues and Hossmann (1971) established that inhibition of protein synthesis occurred in neurons after brain I/R, likely involving a defect in translation initiation.…”

Section: Summary Of Translation Arrest After Ischemia and Reperfusionmentioning

confidence: 99%

Irreversible Translation Arrest in the Reperfused Brain

DeGracia

2006

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

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.

show abstract

Section: Summary Of Translation Arrest After Ischemia and Reperfusionmentioning

confidence: 99%

Irreversible Translation Arrest in the Reperfused Brain

DeGracia

2006

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

“…One puts the emphasis on a sustained perturbation of the signal transduction pathway, ie, the sequence of events that starts with the activation of receptors for EAAs and neurotrophins, continues with the activation or deactivation of protein kinases and phosphatases, and ends with an altered activity of major response elements, mainly those regulating gene expression and protein. [78][79][80] One feels intuitively that nuclear events, particularly if they involve fragmentation of DNA, could be devastating for cell survival. Furthermore, a sustained suppression of protein synthesis could be equally harmful since it bereaves the cells of molecules required for survival, such as antioxidative enzymes and trophic factors.…”

Section: Calcium and Delayed Neuronal Deathmentioning

confidence: 99%

Calcium in Ischemic Cell Death

Kristián

Siesjö

1998

Stroke

739

428

View full text Add to dashboard Cite

Background-This review article deals with the role of calcium in ischemic cell death. A calcium-related mechanism was proposed more than two decades ago to explain cell necrosis incurred in cardiac ischemia and muscular dystrophy. In fact, an excitotoxic hypothesis was advanced to explain the acetylcholine-related death of muscle end plates. A similar hypothesis was proposed to explain selective neuronal damage in the brain in ischemia, hypoglycemic coma, and status epilepticus. Summary of Review-The original concepts encompass the hypothesis that cell damage in ischemia-reperfusion is due to enhanced activity of phospholipases and proteases, leading to release of free fatty acids and their breakdown products and to degradation of cytoskeletal proteins. It is equally clear that a coupling exists between influx of calcium into cells and their production of reactive oxygen species, such as ⅐O 2 Ϫ , H 2 O 2 , and ⅐OH. Recent results have underscored the role of calcium in ischemic cell death. A coupling has been demonstrated among glutamate release, calcium influx, and enhanced production of reactive metabolites such as ⅐O 2 Ϫ , ⅐OH, and nitric oxide. It has become equally clear that the combination of ⅐O 2 Ϫ and nitric oxide can yield peroxynitrate, a metabolite with potentially devastating effects. The mitochondria have again come into the focus of interest. This is because certain conditions, notably mitochondrial calcium accumulation and oxidative stress, can trigger the assembly (opening) of a high-conductance pore in the inner mitochondrial membrane. The mitochondrial permeability transition (MPT) pore leads to a collapse of the electrochemical potential for H ϩ , thereby arresting ATP production and triggering production of reactive oxygen species. The occurrence of an MPT in vivo is suggested by the dramatic anti-ischemic effect of cyclosporin A, a virtually specific blocker of the MPT in vitro in transient forebrain ischemia. However, cyclosporin A has limited effect on the cell damage incurred as a result of 2 hours of focal cerebral ischemia, suggesting that factors other than MPT play a role. It is discussed whether this could reflect the operation of phospholipase A 2 activity and degradation of the lipid skeleton of the inner mitochondrial membrane. Conclusions-Calcium is one of the triggers involved in ischemic cell death, whatever the mechanism. (Stroke.1998;29:705-718.)Key Words: calcium Ⅲ cerebral ischemia Ⅲ free radicals Ⅲ mitochondria T he calcium hypothesis of ischemic cell death was originally launched to explain the relationship between excessive calcium influx and the cell damage that is incurred in myocardial ischemia 1 as well as in muscle dystrophy. 2 In fact, studies conducted at that time led to the formulation of an excitotoxic hypothesis, predicting that excessive release of acetylcholine at the motor end plate was what caused damage to skeletal muscle. 3,4 The work performed at that time on ischemic muscle damage was almost visionary since it forestalled the pivotal role of release o...

show abstract

“…The mechanisms of ischemic cell damage are still a matter of debate (for reviews, see Bazan et al, 1993;Diemer et al, 1993;Hossmann, 1993;Paschen et al, 1993;Pulsinelli et al, 1993 ;Watson, 1993 ;Wieloch et al, 1993) . One way to study mechanisms of ischemic cell damage is to use agonists or antagonists of specific biochemical pathways or physiological reactions and, thus, to manipulate the density of ischemic cell damage after transient cerebral ischemia .…”

mentioning

confidence: 99%

Comparison of In Vitro Ischemia‐Induced Disturbances in Energy Metabolism and Protein Synthesis in the Hippocampus of Rats and Gerbils

Paschen

Djuričić

1995

Journal of Neurochemistry

View full text Add to dashboard Cite

To elucidate whether the high sensitivity of gerbil compared with rat hippocampus to metabolic stress results from tissue‐specific or hemodynamic factors, ischemia‐induced metabolic disturbances [energy metabolism and protein synthesis rate (PSR)] were studied using the in vitro model of the hippocampal slice preparation. At the end of in vitro ischemia, ATP content was measured in individual slices with HPLC. In other groups of slices, PSR was measured after 120 min of recovery after in vitro ischemia. ATP breakdown was almost identical in rat and gerbil slices at all temperatures (37°C, 34°C, or 31°C) and periods of ischemia (5, 10, or 15 min) studied. In contrast to the identical rate of ATP depletion during ischemia, however, postischemic disturbances in PSR were significantly increased in gerbil slices compared with rat slices and this relationship was stable after different periods of ischemia and at different incubation temperatures. The results illustrate that the pattern of ischemia‐induced disturbances observed in vivo can also be reproduced using the in vitro model of hippocampal slice preparation, as evidenced by the postischemic disturbance in PSR. It is concluded that comparison of the extent of metabolic disturbances in gerbil and rat hippocampal slices after transient in vitro ischemia may help to elucidate the mechanisms of ischemic cell damage.

show abstract

Chapter 12 Protein phosphorylation and the regulation of mRNA translation following cerebral ischemia

Cited by 26 publications

References 91 publications

Irreversible Translation Arrest in the Reperfused Brain

Irreversible Translation Arrest in the Reperfused Brain

Calcium in Ischemic Cell Death

Comparison of In Vitro Ischemia‐Induced Disturbances in Energy Metabolism and Protein Synthesis in the Hippocampus of Rats and Gerbils

Contact Info

Product

Resources

About