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首页> 外文期刊>Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism >Irreversible translation arrest in the reperfused brain.
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Irreversible translation arrest in the reperfused brain.

机译：不可逆的翻译停滞在再灌注的大脑中。

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摘要

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 supportingthis 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.
机译：不可逆的翻译停滞发生在再灌注的神经元中，它将因延迟的神经元死亡而死亡。现在已经认识到，蛋白质合成的抑制是真核细胞对外源应激源的一般反应。确实，应激诱导的翻译停滞可以被视为细胞应激反应的一部分，由与应激诱导的转录机制协同工作的起始，维持和终止阶段组成。在此框架内，我们审查了再灌注神经元的翻译停滞。该框架提供了一个基础，以认识到真核生物起始因子2的α亚基的磷酸化是翻译停滞的起始剂，并且是指示神经元应激反应激活的关键标志物。但是，eIF2α磷酸化是可逆的。应激诱导的翻译停滞的其他阶段似乎特别是在缺血性脆弱神经元群体中导致不可逆的翻译停滞。我们详细说明了支持这一观点的两条证据。首先，缺血作为一种应激刺激，在再灌注4至6小时后会诱导不可逆的共翻译蛋白错误折叠和聚集，从而使蛋白合成机制陷入功能失活的蛋白聚集体中。其次，缺血和再灌注导致应激颗粒（SGs​​）发生修饰，这些颗粒隔离功能不活跃的48S预启动复合物以维持翻译停滞。在以后的再灌注期间，这些机制可能会融合，从而使SGs被隔离在蛋白质聚集体中。这些机制导致功能活性核糖体的消除，并阻止选择性脆弱神经元中蛋白质合成的恢复。因此，将翻译停滞识别为内源性细胞应激反应途径的一部分将有助于理解缺血后翻译停滞的复杂性。

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