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

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.

• Authors: Jin Gao, Xiao-Yu Kang, Shen Sun, Li Li, Dian-Shuai Gao
• Journal: Journal of molecular neuroscience : MN (J Mol Neurosci) Vol. 70 Issue 3 Pg. 328-339 (Mar 2020) ISSN: 1559-1166 [Electronic] United States
• PMID: 31720997 (Publication Type: Journal Article)

Chemical References

• Glial Cell Line-Derived Neurotrophic Factor
• Akt1 protein, rat
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Cell Line, Tumor
• Glial Cell Line-Derived Neurotrophic Factor (genetics, metabolism)
• Neuroblastoma (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Signal Transduction