ALK5信号通路通过Gadd45b介导大鼠脑缺血/再灌注后的神经发生和功能恢复。,Cell Death & Disease

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ALK5信号通路通过Gadd45b介导大鼠脑缺血/再灌注后的神经发生和功能恢复。
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-05-01 , DOI: 10.1038/s41419-019-1596-z
Keming Zhang ₁ , Qinbin Zhang ₁ , Jing Deng ₂ , Jinfang Li ₁ , Jiani Li ₁ , Lan Wen ₃ , Jingxi Ma ₂ , Changqing Li ₁

Affiliation

转化生长因子β（TGF-β）在脑损伤，尤其是脑缺血中起关键作用；然而，除其神经保护作用外，其在调节神经发生中的作用尚不清楚。TGF-β的作用方式不同。最重要的典型TGF-β活性涉及TGF-β受体I（TβRI）或激活素受体样激酶5（ALK5）信号传导途径。ALK5信号传导是成人神经发生的主要决定因素。在我们以前的研究中，中风后生长停滞和DNA损伤蛋白45b（Gadd45b）介导了轴突可塑性。在这里，我们假设ALK5信号通过Gadd45b调节脑缺血/再灌注（I / R）后的神经可塑性和神经功能恢复。首先，在大脑中动脉闭塞/再灌注（MCAO / R）大鼠中ALK5表达显着增加。然后，我们在体内用慢病毒（LV）敲低或过度表达了ALK5。ALK5组合式降低轴突和树突状可塑性，并伴随神经功能恢复的减少。相反，ALK5的过表达显着增加了神经发生以及功能恢复。此外，ALK5通过调节Smad2 / 3磷酸化介导Gadd45b蛋白水平。最后，ALK5与Gadd45b共免疫沉淀。我们的研究结果表明，ALK5信号通路在介导脑缺血后通过Gadd45b介导神经可塑性和神经功能恢复中起着关键作用，代表了脑I / R损伤的新潜在靶点。ALK5过表达显着增加了神经发生以及功能恢复。此外，ALK5通过调节Smad2 / 3磷酸化介导Gadd45b蛋白水平。最后，ALK5与Gadd45b共免疫沉淀。我们的研究结果表明，ALK5信号通路在介导脑缺血后通过Gadd45b介导神经可塑性和神经功能恢复中起着关键作用，代表了脑I / R损伤的新潜在靶点。ALK5过表达显着增加了神经发生以及功能恢复。此外，ALK5通过调节Smad2 / 3磷酸化介导Gadd45b蛋白水平。最后，ALK5与Gadd45b共免疫沉淀。我们的研究结果表明，ALK5信号通路在介导脑缺血后通过Gadd45b介导神经可塑性和神经功能恢复中起着关键作用，代表了脑I / R损伤的新潜在靶点。

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ALK5 signaling pathway mediates neurogenesis and functional recovery after cerebral ischemia/reperfusion in rats via Gadd45b.

Transforming growth factor β (TGF-β) serves critical functions in brain injury, especially in cerebral ischemia; however, apart from its neuroprotective effects, its role in regulating neurogenesis is unclear. TGF-β acts in different ways; the most important, canonical TGF-β activity involves TGF-β receptor I (TβRI) or the activin receptor-like kinase 5 (ALK5) signaling pathway. ALK5 signaling is a major determinant of adult neurogenesis. In our previous studies, growth arrest and DNA damage protein 45b (Gadd45b) mediated axonal plasticity after stroke. Here, we hypothesized that ALK5 signaling regulates neural plasticity and neurological function recovery after cerebral ischemia/reperfusion (I/R) via Gadd45b. First, ALK5 expression was significantly increased in middle cerebral artery occlusion/reperfusion (MCAO/R) rats. Then, we knocked down or overexpressed ALK5 with lentivirus (LV) in vivo. ALK5 knockdown reduced axonal and dendritic plasticity, with a concomitant decrease in neurological function recovery. Conversely, ALK5 overexpression significantly increased neurogenesis as well as functional recovery. Furthermore, ALK5 mediated Gadd45b protein levels by regulating Smad2/3 phosphorylation. Finally, ALK5 coimmunoprecipitated with Gadd45b. Our results suggested that the ALK5 signaling pathway plays a critical role in mediating neural plasticity and neurological function recovery via Gadd45b after cerebral ischemia, representing a new potential target for cerebral I/R injury.

更新日期：2019-05-16

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