Shank3 ameliorates neuronal injury after cerebral ischemia/reperfusion via inhibiting oxidative stress and inflammation
Hongchen Zhang,
Yuan Feng,
Yanfang Si,
Chuanhao Lu,
Juan Wang,
Shiquan Wang,
Liang Li,
Wenyu Xie,
Zheming Yue,
Jia Yong,
Shuhui Dai,
Lei Zhang,
Xia Li
Affiliations
Hongchen Zhang
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
Yuan Feng
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
Yanfang Si
Department of Ophthalmology, The Eighth Medical Center, Affiliated to the Senior Department of Ophthalmology, The Third Medical Center, Chinese People's Liberation Army General Hospital, Beijing, 100091, China
Chuanhao Lu
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
Juan Wang
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
Shiquan Wang
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
Liang Li
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
Wenyu Xie
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
Zheming Yue
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
Jia Yong
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
Shuhui Dai
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China; National Translational Science Center for Molecular Medicine and Department of Cell Biology, Fourth Military Medical University, Xi'an, 710032, China; Corresponding author. Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Rd, Xi'an, 710032, China.
Lei Zhang
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China; Corresponding author. Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Rd, Xi'an, 710032, China.
Xia Li
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China; Corresponding author. Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Rd, Xi'an, 710032, China.
Shank3, a key molecule related to the development and deterioration of autism, has recently been found to downregulate in the murine brain after ischemia/reperfusion (I/R). Despite this discovery, however, its effects on neuronal injury and the mechanism underlying the effects remain to be clarified. To address this, in this study, based on genetically modified mice models, we revealed that the expression of Shank3 showed a time-dependent change in murine hippocampal neurons after I/R, and that conditional knockout (cko) of Shank3 in neurons resulted in aggravated neuronal injuries. The protective effects of Shank3 against oxidative stress and inflammation after I/R were achieved through direct binding STIM1 and subsequent proteasome-mediated degradation of STIM1. The STIM1 downregulation induced the phosphorylation of downstream Nrf2 Ser40, which subsequently translocated to the nucleus, and further increased the expression of antioxidant genes such as NQO1 and HO-1 in HT22 cells. In vivo, the study has further confirmed that double knockout of Shank3 and Stim1 alleviated oxidative stress and inflammation after I/R in Shank3cko mice. In conclusion, the present study has demonstrated that Shank3 interacts with STIM1 and inhibits post-I/R neuronal oxidative stress and inflammatory response via the Nrf2 pathway. This interaction can potentially contribute to the development of a promising method for I/R treatment.
