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Int J Mol Sci. 2019 Apr 10;20(7). pii: E1772. doi: 10.3390/ijms20071772.

Rhododendrin-Induced RNF146 Expression via Estrogen Receptor β Activation is Cytoprotective Against 6-OHDA-Induced Oxidative Stress.

Author information

1
Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, Gyeonggi-do 440-746, Korea. hjung93@skku.edu.
2
Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, Gyeonggi-do 440-746, Korea. zysu0728@skku.edu.
3
National Development Institute of Korean Medicine, Gyeongsan 38540, Korea. npb0391@nikom.or.kr.
4
National Development Institute of Korean Medicine, Gyeongsan 38540, Korea. meanglae@nikom.or.kr.
5
College of Pharmacy, Gachon University, Incheon 21936, Korea. jinha89@daum.net.
6
College of Pharmacy, Gachon University, Incheon 21936, Korea. hjmaeng@gachon.ac.kr.
7
Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, Gyeonggi-do 440-746, Korea. ylee69@skku.edu.

Abstract

Ring finger protein 146 (RNF146) is an E3 ubiquitin ligase whose activity prevents poly (ADP-ribose) polymerase 1 (PARP1)-dependent neurodegeneration in Parkinson's disease (PD). Previously, we reported that rhododendrin is a chemical inducer that increases RNF146 expression. However, the molecular mechanism of rhododendrin-induced RNF146 expression is largely unknown and its translational application for the treatment of Parkinson's disease remains unexplored. Here we found that rhododendrin increased RNF146 expression via estrogen receptor β (ERβ) activation. Rhododendrin stimulated ERβ nuclear translocation and binding to the RNF146 promoter, thereby enhancing its transcription. Rhododendrin is cytoprotective against 6-hydroxydopamine (6-OHDA)-induced cell death, which is largely dependent on ERβ activity and RNF146 expression. Finally, we demonstrated that rhododendrin treatment resulted in RNF146 expression in dopaminergic neurons in mice. Moreover, dopaminergic neuron viability was markedly enhanced by pretreatment with rhododendrin in 6-OHDA-induced mouse models for PD. Our findings indicate that estrogen receptor activation plays a neuroprotective role and that rhododendrin could be a potential therapeutic agent in preventing PARP1-dependent dopaminergic cell loss in PD.

KEYWORDS:

Parkinson’s disease; RNF146; dopaminergic neurodegeneration; estrogen receptor; poly (ADP-ribose); rhododendrin

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