Nrf2-mediated neuroprotection by MANF against 6-OHDA-induced cell damage via PI3K/AKT/GSK3β pathway

  • Exp Gerontol. 2017 Dec 15;100:77-86. doi: 10.1016/j.exger.2017.10.021.
Jingxing Zhang  1 ,  Weifang Tong  1 ,  Hui Sun  1 ,  Ming Jiang  2 ,  Yijue Shen  1 ,  Yigang Liu  1 ,  Hua Gu  3 ,  Jia Guo  2 ,  Jianmin Fang  4 ,  Lingjing Jin  5
Affiliations
  • 1. Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai 200065, PR China.
  • 2. Biomedical Research Center, Tongji University Suzhou Institute, Building 2198 Jinfeng Road, Wuzhong District, Suzhou, Jiangsu 215101, PR China.
  • 3. School of Life Science and Technology, Tongji University, 1239 Siping Road, Shang hai 200092, PR China.
  • 4. School of Life Science and Technology, Tongji University, 1239 Siping Road, Shang hai 200092, PR China; Biomedical Research Center, Tongji University Suzhou Institute, Building 2198 Jinfeng Road, Wuzhong District, Suzhou, Jiangsu 215101, PR China. Electronic address: [email protected].
  • 5. Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai 200065, PR China. Electronic address: [email protected].
PMID: 29079145 DOI: 10.1016/j.exger.2017.10.021
Abstract

Oxidative stress and Apoptosis are thought to be broadly involved in the pathogenesis of Parkinson's disease. We previously reported that Mesencephalic astrocyte-derived neurotrophic factor (MANF) possesses anti-oxidation and anti-apoptotic effects against 6-OHDA-induced neurotoxicity, but the specific molecular mechanism remains unclear. In this study, we showed that MANF up-regulates the expression of nuclear factor erythroid 2-related factor (Nrf2) and promotes its translocation into the nucleus. The anti-oxidation and anti-apoptotic effects of MANF could be partially blocked by inhibitor or shRNA-mediated knockdown of Nrf2. Furthermore, MANF activated phospoinositide-3-kinase (PI3K)/Akt signaling and suppressed glycogen synthase kinase (GSK3β) activation. PI3K Inhibitor (LY49002) abolished effects of MANF on Akt phosphorylation, GSK3β inactivation, Nrf2 nuclear translocation and subsequently abrogated MANF-mediates cytoprotection. Collectively, our findings indicated that MANF-mediated protection against 6-OHDA-induced cytotoxicity by potentiating the Nrf2-related survival mechanism through the PI3K/Akt/GSK3β pathway.

Keywords
Apoptosis; MANF; Nrf2; Oxidative stress; PI3K/Akt/GSK3β; SH-SY5Y cells.
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