Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, Gyeonggi-do 440-746, Korea.
National Development Institute of Korean Medicine, Gyeongsan 38540, Korea.
Int J Mol Sci. 2019 Apr 10;20(7):1772. doi: 10.3390/ijms20071772.
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.
环指蛋白 146（RNF146）是一种 E3 泛素连接酶，其活性可防止帕金森病（PD）中多聚（ADP-核糖）聚合酶 1（PARP1）依赖性神经退行性变。先前，我们报道了杜鹃素是一种化学诱导剂，可增加 RNF146 的表达。然而，杜鹃素诱导 RNF146 表达的分子机制在很大程度上尚不清楚，其在帕金森病治疗中的翻译应用仍未得到探索。在这里，我们发现杜鹃素通过雌激素受体 β（ERβ）的激活来增加 RNF146 的表达。杜鹃素刺激 ERβ核易位并与 RNF146 启动子结合，从而增强其转录。杜鹃素对 6-羟多巴胺（6-OHDA）诱导的细胞死亡具有细胞保护作用，这在很大程度上依赖于 ERβ 活性和 RNF146 的表达。最后，我们证明杜鹃素处理可导致小鼠多巴胺能神经元中 RNF146 的表达。此外，在帕金森病 6-OHDA 诱导的小鼠模型中，用杜鹃素预处理可明显增强多巴胺能神经元的活力。我们的研究结果表明，雌激素受体的激活发挥了神经保护作用，并且杜鹃素可能是预防 PARP1 依赖性多巴胺能神经元丢失的潜在治疗剂。
