Journal
EXPERIMENTAL GERONTOLOGY
Volume 100, Issue -, Pages 77-86Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.exger.2017.10.021
Keywords
MANF; Nrf2; PI3K/Akt/GSK3 beta; Apoptosis; Oxidative stress; SH-SY5Y cells
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Funding
- National Major Scientific and Technological Special Project for Significant New Drugs Development [2014ZX09102043-003]
- National Natural Science Foundation of China [81371403, 81572234]
- Shanghai Science and Technology Commission [13JC1401102]
- Natural Science Foundation of Jiangsu Province of China [BK20140275]
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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 (GSK3 beta) activation. PI3K inhibitor (LY49002) abolished effects of MANF on AKT phosphorylation, GSK3 beta 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/GSK3 beta pathway.
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