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

Jingxing Zhang1, Weifang Tong1, Hui Sun1

  • 1Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai 200065, PR China.

Experimental Gerontology
|October 29, 2017
PubMed

Insights

Mesencephalic astrocyte-derived neurotrophic factor (MANF) protects against Parkinson's disease neurotoxicity by activating the Nrf2 pathway. This involves the PI3K/Akt/GSK3β signaling cascade, enhancing cellular survival mechanisms.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Parkinson's disease pathogenesis involves oxidative stress and apoptosis.
  • Mesencephalic astrocyte-derived neurotrophic factor (MANF) exhibits neuroprotective effects.
  • The precise molecular mechanisms underlying MANF's neuroprotection are not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanism of MANF's anti-oxidative and anti-apoptotic effects against 6-OHDA-induced neurotoxicity.
  • To investigate the role of Nuclear factor erythroid 2-related factor (Nrf2) and the PI3K/Akt/GSK3β pathway in MANF-mediated neuroprotection.

Main Methods:

  • Investigated MANF's effect on Nrf2 expression and nuclear translocation.
  • Utilized Nrf2 inhibitors and shRNA to assess its role in MANF's protective effects.
  • Examined the involvement of the phosphoinositide-3-kinase (PI3K)/Akt/glycogen synthase kinase (GSK3β) signaling pathway.
  • Used a PI3K inhibitor (LY49002) to block signaling and assess downstream effects.

Main Results:

  • MANF up-regulates Nrf2 expression and promotes its nuclear translocation.
  • Nrf2 knockdown partially abrogates MANF's anti-oxidative and anti-apoptotic effects.
  • MANF activates PI3K/Akt signaling and inactivates GSK3β.
  • Inhibition of PI3K blocks MANF-induced Akt phosphorylation, GSK3β inactivation, Nrf2 translocation, and cytoprotection.

Conclusions:

  • MANF confers protection against 6-OHDA-induced cytotoxicity via the PI3K/Akt/GSK3β pathway.
  • This pathway potentiates the Nrf2-related survival mechanism, highlighting a novel therapeutic target for Parkinson's disease.
  • MANF's neuroprotective action is mediated through the modulation of oxidative stress and apoptosis via Nrf2 activation.
Keywords:
ApoptosisMANFNrf2Oxidative stressPI3K/Akt/GSK3βSH-SY5Y cells

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