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. Epub 2017 Oct 25.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Cell Line, Tumor
  • Cytoprotection
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Humans
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Nerve Growth Factors / pharmacology*
  • Neuroprotective Agents / pharmacology*
  • Oxidative Stress / drug effects*
  • Oxidopamine
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects*


  • MANF protein, human
  • NF-E2-Related Factor 2
  • Nerve Growth Factors
  • Neuroprotective Agents
  • Oxidopamine
  • Phosphatidylinositol 3-Kinases
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt