Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury Involvement of PARK2-dependent mitophagy
Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury Involvement of PARK2-dependent mitophagy
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衣霉素和毒胡萝卜素诱导的内质网应激可预防短暂性缺血性脑损伤 PARK2 依赖性线粒体自噬的参与
DOI：
10.4161/auto.32136
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发表时间：
2014-10-01
期刊：
影响因子：
13.3
通讯作者：
Chen, Zhong
中科院分区：
文献类型：
--
作者：
Zhang, Xiangnan;Yuan, Yang;Chen, Zhong
短暂性脑缺血导致内质网（ER）应激。然而，ER应激在脑缺血中的作用尚不清楚。为了解决这个问题，将ER应激激活剂衣霉素（TM）和毒胡萝卜素（TG）施用给短暂大脑中动脉闭塞（tMCAO）小鼠和氧-葡萄糖剥夺-再灌注（OGD-Rep.）处理过的神经元TM和TG均显示出对缺血诱导的脑损伤的显著保护，如通过减少脑梗死体积和增加缺血组织中的葡萄糖摄取率所揭示的。在OGD-Rep.中，4-PBA，ER应激释放机制，抵消了TM和TG的神经元保护作用，这也支持ER应激在短暂脑缺血中的保护作用。敲除ER应力传感器Eif 2s 1，其被TM和TG进一步激活，降低了OGD-Rep。诱导神经元细胞死亡。此外，TM和TG都防止PARK 2丢失，促进其向线粒体的募集，并在缺血后再灌注期间激活线粒体自噬。TM和TG的神经保护作用通过自噬抑制（3-甲基腺嘌呤和Atg 7敲低）以及Park 2沉默来逆转。Park 2（+/-）小鼠的神经保护作用也减弱。此外，Eif 2s 1和下游Atf 4沉默减少PARK 2表达，损害线粒体自噬诱导，并抵消神经保护。总而言之，本研究表明TM和TG诱导的ER应激可保护短暂性缺血性脑损伤。PARK 2介导的线粒体自噬可能是内质网应激的保护机制之一。这些发现可能为通过内质网应激激活诱导线粒体自噬来挽救缺血脑提供一种新的策略。
Transient cerebral ischemia leads to endoplasmic reticulum (ER) stress. However, the contributions of ER stress to cerebral ischemia are not clear. To address this issue, the ER stress activators tunicamycin (TM) and thapsigargin (TG) were administered to transient middle cerebral artery occluded (tMCAO) mice and oxygen-glucose deprivation-reperfusion (OGD-Rep.)-treated neurons. Both TM and TG showed significant protection against ischemia-induced brain injury, as revealed by reduced brain infarct volume and increased glucose uptake rate in ischemic tissue. In OGD-Rep.-treated neurons, 4-PBA, the ER stress releasing mechanism, counteracted the neuronal protection of TM and TG, which also supports a protective role of ER stress in transient brain ischemia. Knocking down the ER stress sensor Eif2s1, which is further activated by TM and TG, reduced the OGD-Rep.-induced neuronal cell death. In addition, both TM and TG prevented PARK2 loss, promoted its recruitment to mitochondria, and activated mitophagy during reperfusion after ischemia. The neuroprotection of TM and TG was reversed by autophagy inhibition (3-methyladenine and Atg7 knockdown) as well as Park2 silencing. The neuroprotection was also diminished in Park2(+/-) mice. Moreover, Eif2s1 and downstream Atf4 silencing reduced PARK2 expression, impaired mitophagy induction, and counteracted the neuroprotection. Taken together, the present investigation demonstrates that the ER stress induced by TM and TG protects against the transient ischemic brain injury. The PARK2-mediated mitophagy may be underlying the protection of ER stress. These findings may provide a new strategy to rescue ischemic brains by inducing mitophagy through ER stress activation.