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Autophagy. 2014 Oct 1;10(10):1801-13. doi: 10.4161/auto.32136. Epub 2014 Aug 5.

Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury: Involvement of PARK2-dependent mitophagy.

Author information

1
Department of Pharmacology; Key Laboratory of Medical Neurobiology of the Ministry of Health of China; Zhejiang Province Key Laboratory of Neurobiology; College of Pharmaceutical Sciences; Zhejiang University; Hangzhou, China; Collaborative Innovation Center for Infectious Diseases; Zhejiang University; Hangzhou, China.
2
Department of Pharmacology; Key Laboratory of Medical Neurobiology of the Ministry of Health of China; Zhejiang Province Key Laboratory of Neurobiology; College of Pharmaceutical Sciences; Zhejiang University; Hangzhou, China.
3
Zhejiang Provincial Key Laboratory of Medical Genetics; School of Life Sciences; Wenzhou Medical College; Wenzhou, China.
4
Department of Pharmacology; Key Laboratory of Medical Neurobiology of the Ministry of Health of China; Zhejiang Province Key Laboratory of Neurobiology; College of Pharmaceutical Sciences; Zhejiang University; Hangzhou, China; Department of Pharmacy; the Second Affiliated Hospital; School of Medicine; Zhejiang University; Hangzhou, China.
5
Department of Pharmacy; the Second Affiliated Hospital; School of Medicine; Zhejiang University; Hangzhou, China.
6
State Key Laboratory of Medical Genetics; Central South University; Changsha, China.

Abstract

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.

KEYWORDS:

PARK2; cerebral ischemia; endoplasmic reticulum stress; mitophagy; neuroprotection

PMID:
25126734
PMCID:
PMC4198364
DOI:
10.4161/auto.32136
[Indexed for MEDLINE]
Free PMC Article

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