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MES23.5 DA Immortalized Neuroblastoma Cells Self-protect Against Early Injury by Overexpressing Glial Cell–derived Neurotrophic Factor via Akt1/Eya1/Six2 Signaling

  • Jin Gao
  • Xiao-yu Kang
  • Shen Sun
  • Li Li
  • Dian-shuai GaoEmail author
Article
  • 59 Downloads

Abstract

Injured neurons can initiate their own neurotoxin-induced repair mechanisms by expressing protective genes and activating specific intracellular signal transduction pathways. Although glial cell–derived neurotrophic factor (GDNF) plays a key role in the repair of dopaminergic (DA) neurons, whether there is high expression of GDNF in DA neurons at an early stage of injury has not yet been reported. In this study, neurotoxin-induced GDNF overexpression was detected for the first time in MES23.5 DA immortalized neuroblastoma (MES23.5 DA) cells soon after 6-hydroxydopamine (6-OHDA) treatment. We also observed that the phosphorylation of Akt1, a member of the protein kinase B family, was increased. Further studies showed that activated Akt1 increased the phosphorylation of the protein phosphatase Eya1, which is a member of the eyes absent (Eya) family of transcriptional cofactors. Then, activated Eya1 decreased the phosphorylation of the sine oculis–related homeobox 2 (Six2) transcription factor. In addition, chromatin immunoprecipitation coupled with quantitative polymerase chain reaction (ChIP-qPCR) revealed that Six2 promoted GDNF transcription in MES23.5 DA cells by directly binding to the GDNF promoter. Finally, we showed that inhibiting neurotoxin-induced GDNF overexpression increased MES23.5 DA cell death, while promoting GDNF expression via Six2 overexpression decreased DA neuronal death. These results suggest that MES23.5 DA cells with early 6-OHDA-induced injury can promote the overexpression of GDNF by activating the Akt1/Eya1/Six2 signaling pathway, and this overexpression of GDNF has protective effects on injured MES23.5 DA cells. Hence, this study highlights a new target for drug development for the treatment of Parkinson’s disease.

Keywords

Glial cell line–derived neurotrophic factor Neurotoxin-induced overexpression Akt1 Eya1 Six2 

Notes

Funding Information

This work was supported by the Natural Science Foundation of Jiangsu Province (grant number SBK2017042600), Key Laboratory of New Drug Research and Clinical Pharmacy of Jiangsu Province (grant number KF-XY201403), and National Natural Science Foundation Project (grant number H1618).

Compliance with Ethical Standards

Competing Interests

The authors declare that they have no competing interests.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Neurobiology and Cell Biology, Xuzhou Key Laboratory of Neurobiology, Key Laboratory of New Drug Research and Clinical Pharmacy of Jiangsu ProvinceXuzhou Medical UniversityXuzhouChina

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