Cerebral ischemia–reperfusion injury is pivotal in the development of multiple-subcellular organelle and tissue injury after acute ischemic stroke. Recently, the Golgi apparatus (GA) has been shown to be a key subcellular organelle that plays an important role in neuroprotection against oxygen–glucose deprivation/reperfusion (OGD/R) injury. PAQR3, a scaffold protein exclusively localized in the GA, was originally discovered as a potential tumor suppressor protein. PAQR3 acts as a spatial regulator of Raf-1 that binds Raf-1 and sequesters it to the GA, where it negatively modulates the Ras/Raf/MEK/ERK signaling pathway in tumor models. Studies suggest that suppression of the ERK pathway can alleviate OGD/R-induced cell apoptosis. However, whether PAQR3 has potential effects on ischemic stroke and the underlying mechanism(s) remain unexplored. The current study is the first to show that PAQR3 was significantly downregulated in mouse neuroblastoma (N2A) cells upon OGD/R exposure, both at the mRNA and protein levels. Compared to that in controls, the mRNA level of PAQR3 began to decline at 0 h (0 h) after reperfusion, while the protein level began to decline at 4 h. Furthermore, overexpression of PAQR3 reduced OGD/R-induced apoptosis. The mRNA and protein levels of total ERK1 and ERK2 were unaltered, while activated p-ERK1 and p-ERK2 were decreased in N2A cells transfected with a PAQR3 expression vector after OGD for 4 h plus 24 h of reperfusion. Collectively, these data indicated that increased PAQR3 expression protected against OGD/R-induced apoptosis possibly by inhibiting the ERK signaling pathway. Therefore, PAQR3 might be a new attractive target in the treatment of OGD/R insult, and the underlying mechanism will pave the way for its potential experimental and clinical application.

中文翻译：

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PAQR3可通过N2A细胞中的ERK信号通路防止氧葡萄糖剥夺/再灌注引起的损伤。

脑缺血再灌注损伤在急性缺血性中风后在多亚细胞细胞器的发展和组织损伤中起着关键作用。最近，高尔基体（GA）被证明是关键的亚细胞器，在抗氧-葡萄糖剥夺/再灌注（OGD / R）损伤的神经保护中起重要作用。PAQR3是仅位于GA中的一种支架蛋白，最初被发现是一种潜在的肿瘤抑制蛋白。PAQR3充当Raf-1的空间调节剂，该Raf-1结合Raf-1并将其螯合至GA，从而在肿瘤模型中对Ras / Raf / MEK / ERK信号通路产生负调控。研究表明，抑制ERK途径可以减轻OGD / R诱导的细胞凋亡。但是，PAQR3是否对缺血性中风具有潜在影响，其潜在机制尚待探讨。当前的研究是第一个显示在OGD / R暴露后，mRNA和蛋白水平上的PAQR3在小鼠神经母细胞瘤（N2A）细胞中均显着下调的研究。与对照组相比，PAQR3的mRNA水平在再灌注后0 h（0 h）开始下降，而蛋白水平在4 h开始下降。此外，PAQR3的过表达减少了OGD / R诱导的细胞凋亡。OGD作用4 h + 24 h再灌注PAQR3表达载体转染的N2A细胞中，总ERK1和ERK2的mRNA和蛋白水平保持不变，而活化的p-ERK1和p-ERK2则降低。总体而言，这些数据表明增加的PAQR3表达可能通过抑制ERK信号通路来保护免受OGD / R诱导的细胞凋亡。因此，PAQR3可能是治疗OGD / R损伤的新靶标，