PDF(Pubmed)
Abstract：
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 Acanthopanax sessiliflorus to prevent PD symptoms. The results show that in the 6-hydroxydopamine (6-OHDA) model, CSS pretreatment can effectively alleviate the reactive oxygen species generation and apoptosis of SH-SY5Y cells, thereby lessening the defects in the C. elegans 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.
摘要：
已知多巴胺（DA）神经元的变性与衰老引起的线粒体生物发生缺陷有关，环境因素,或基因突变，导致帕金森病（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发生的策略是一个有前途的方向。这项研究评估了在刺五加叶中鉴定出的合成花香苷（CSS）预防PD症状的功效。结果表明,在6-羟基多巴胺(6-OHDA)模型中,CSS预处理能有效缓解SH-SY5Y细胞的活性氧生成和凋亡,从而减少了秀丽隐杆线虫模型中的缺陷，包括DA神经元变性，多巴胺介导的食物敏感性行为障碍，缩短寿命。机械上,我们发现CSS可以恢复增殖物激活受体γ辅激活因子-1-α（PGC-1α）的表达，线粒体生物发生的关键分子，及其下游相关基因被6-OHDA抑制。我们进一步证实，这是由于Parkin的活性增强，导致PGC-1α抑制剂蛋白锌指蛋白746（ZNF746）的泛素化和降解。ParkinsiRNA治疗消除了CSS的这种作用。此外，我们发现CSS抑制6-OHDA诱导的miR-181a的表达，目标是Parkin.转染抗miR-181a和miR-181a模拟物后，CSS逆转6-OHDA诱导的线粒体生物发生减少和细胞凋亡激活的能力被废除。因此,CSS的神经保护作用主要通过调节miR-181a/Parkin/ZNF746/PGC-1α轴来促进线粒体生物发生。CSS可能有机会发展成为PD预防剂。
