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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Ubiquitin proteasome-mediated synaptic reorganization: a novel mechanism underlying rapid ischemic tolerance.
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Ubiquitin proteasome-mediated synaptic reorganization: a novel mechanism underlying rapid ischemic tolerance.

机译：泛素蛋白酶体介导的突触重组：一种基础的快速缺血耐受的新机制。

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摘要

Ischemic tolerance is an endogenous neuroprotective mechanism in brain and other organs, whereby prior exposure to brief ischemia produces resilience to subsequent normally injurious ischemia. Although many molecular mechanisms mediate delayed (gene-mediated) ischemic tolerance, the mechanisms underlying rapid (protein synthesis-independent) ischemic tolerance are relatively unknown. Here we describe a novel mechanism for the induction of rapid ischemic tolerance mediated by the ubiquitin-proteasome system. Rapid ischemic tolerance is blocked by multiple proteasome inhibitors [carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG132), MG115 (carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal), and clasto-lactacystin-beta-lactone]. A proteomics strategy was used to identify ubiquitinated proteins after preconditioning ischemia. We focused our studies on two actin-binding proteins of the postsynaptic density that were ubiquitinated after rapid preconditioning: myristoylated, alanine-rich C-kinase substrate (MARCKS) andfascin. Immunoblots confirm the degradation of MARCKS and fascin after preconditioning ischemia. The loss of actin-binding proteins promoted actin reorganization in the postsynaptic density and transient retraction of dendritic spines. This rapid and reversible synaptic remodeling reduced NMDA-mediated electrophysiological responses and renders the cells refractory to NMDA receptor-mediated toxicity. The dendritic spine retraction and NMDA neuroprotection after preconditioning ischemia are blocked by actin stabilization with jasplakinolide, as well as proteasome inhibition with MG132. Together these data suggest that rapid tolerance results from changes to the postsynaptic density mediated by the ubiquitin-proteasome system, rendering neurons resistant to excitotoxicity.
机译：缺血耐受是脑和其他器官中的内源性神经保护机制，因此先前暴露于短暂缺血会产生对随后的正常伤害性缺血的适应力。尽管许多分子机制介导了延迟的（基因介导的）缺血耐受，但是快速（蛋白质合成无关）缺血耐受的潜在机制却相对未知。在这里，我们描述了一种由泛素-蛋白酶体系统介导的快速缺血耐受诱导的新机制。多种蛋白酶体抑制剂[carbobenzoxy-L-leucyl-L-leucyl-L-leucinal（MG132），MG115（carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal）和clasto-lactacystin-beta可阻止快速缺血耐受-内酯]。蛋白质组学策略用于在预处理缺血后鉴定泛素化的蛋白质。我们的研究集中在快速预处理后遍在泛素化的两种突触后密度的肌动蛋白结合蛋白：肉豆蔻酰化，富含丙氨酸的C激酶底物（MARCKS）和fascin。免疫印迹证实缺血预处理后MARCKS和fascin的降解。肌动蛋白结合蛋白的丧失促进了突触后密度和树突棘的短暂收缩的肌动蛋白重组。这种快速和可逆的突触重塑减少了NMDA介导的电生理反应，并使细胞难于NMDA受体介导的毒性。预处理缺血后的树突棘退缩和NMDA神经保护被jasplakinolide的肌动蛋白稳定作用以及MG132的蛋白酶体抑制作用所阻断。这些数据加在一起表明，快速耐受是由遍在蛋白-蛋白酶体系统介导的突触后密度变化导致的，从而使神经元对兴奋性毒性具有抵抗力。

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