Hsu Yu-Ling, Chen Hui-Jye, Gao Jia-Xin, Yang Ming-Yang, Fu Ru-Huei
Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan.
Department of Laboratory Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan 33305, Taiwan.
Antioxidants (Basel). 2023 Sep 20;12(9):1782. doi: 10.3390/antiox12091782.
The degeneration of dopamine (DA) neurons is known to be associated with defects in mitochondrial biogenesis caused by aging, environmental factors, or mutations in genes, leading to Parkinson's disease (PD). As PD has not yet been successfully cured, the strategy of using small molecule drugs to protect and restore mitochondrial biogenesis is a promising direction. This study evaluated the efficacy of synthetic chiisanoside (CSS) identified in the leaves of to prevent PD symptoms. The results show that in the 6-hydroxydopamine (6-OHDA) model, CSS pretreatment can effectively alleviate the generation and apoptosis of SH-SY5Y cells, thereby lessening the defects in the model including DA neuron degeneration, dopamine-mediated food sensitivity behavioral disorders, and shortened lifespan. Mechanistically, we found that CSS could restore the expression of proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α), a key molecule in mitochondrial biogenesis, and its downstream related genes inhibited by 6-OHDA. We further confirmed that this is due to the enhanced activity of parkin leading to the ubiquitination and degradation of PGC-1α inhibitor protein Zinc finger protein 746 (ZNF746). Parkin siRNA treatment abolished this effect of CSS. Furthermore, we found that CSS inhibited 6-OHDA-induced expression of miR-181a, which targets parkin. The CSS's ability to reverse the 6-OHDA-induced reduction in mitochondrial biogenesis and activation of apoptosis was abolished after the transfection of anti-miR-181a and miR-181a mimics. Therefore, the neuroprotective effect of CSS mainly promotes mitochondrial biogenesis by regulating the miR-181a/Parkin/ZNF746/PGC-1α axis. CSS potentially has the opportunity to be developed into PD prevention agents.
已知多巴胺（DA）神经元的退化与衰老、环境因素或基因突变导致的线粒体生物合成缺陷有关，进而引发帕金森病（PD）。由于PD尚未成功治愈，使用小分子药物保护和恢复线粒体生物合成的策略是一个有前景的方向。本研究评估了从 叶子中鉴定出的合成齐墩果酸（CSS）预防PD症状的效果。结果表明，在6-羟基多巴胺（6-OHDA）模型中，CSS预处理可有效减轻SH-SY5Y细胞的 生成和凋亡，从而减轻该模型中的缺陷，包括DA神经元退化、多巴胺介导的食物敏感性行为障碍和寿命缩短。从机制上讲，我们发现CSS可以恢复线粒体生物合成中的关键分子过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）及其受6-OHDA抑制的下游相关基因的表达。我们进一步证实，这是由于帕金蛋白活性增强导致PGC-1α抑制蛋白锌指蛋白746（ZNF746）的泛素化和降解。帕金蛋白小干扰RNA处理消除了CSS的这种作用。此外，我们发现CSS抑制了6-OHDA诱导的靶向帕金蛋白的miR-181a的表达。转染抗miR-181a和miR-181a模拟物后，CSS逆转6-OHDA诱导的线粒体生物合成减少和凋亡激活的能力被消除。因此，CSS的神经保护作用主要通过调节miR-181a/帕金蛋白/ZNF746/PGC-1α轴来促进线粒体生物合成。CSS有可能被开发成预防PD的药物。
