Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130117, China.
Research Center of Traditional Chinese Medicine, the Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130117, China.
Eur J Pharmacol. 2022 May 5;922:174887. doi: 10.1016/j.ejphar.2022.174887. Epub 2022 Mar 16.
Under pathological conditions, human tau (htau) hyperphosphorylation promotes formation of proteotoxic intracellular amyloid aggregates that may underlie neurodegenerative diseases known as tauopathies, prompting researchers to develop treatments that inhibit htau aggregation as a promising therapeutic strategy. Ginsenosides, the main active constituents of Panax ginseng C. A. Meyer (ginseng), appear to inhibit tau aggregation and disassociation in tauopathy models, although their active components and molecular mechanisms are unknown. Here, we used a novel Caenorhabditis elegans (C. elegans) tauopathy model to identify ginsenoside monomers which may repress htau proteotoxicity. Our findings indicated that ginsenoside Rf prevented tau aggregation and reversed abnormal tau aggregation-induced phenotypes and alleviated neurodegeneration in worms. Notably, deep RNA-seq analysis of ginsenoside Rf-treated and untreated worms with tauopathy revealed that ginsenoside Rf altered expression levels of 24 up- and 36 down-regulated lncRNA transcripts, 32 up- and 22 down-regulated miRNAs and 65 up- and 30 down-regulated mRNA transcripts. Based on GO and KEGG pathway annotation analyses, identified mRNAs, miRNAs and lncRNAs-associated gene targets were functionally related to neuron-related terms (e.g., neuron development, axon and motor neuron axon guidance) and longevity regulating pathways. Importantly, RT-qRCR results suggested that 6 miRNAs (miR-786, miR-2208b, miR-34, miR-241, miR-247 and miR-4805), 8 lncRNAs (MSTRG.20812.2, MSTRG.22617.2, MSTRG.28210.13, MSTRG.5728.12, MSTRG.29708.1, MSTRG.3342.25, MSTRG.3342.31 and MSTRG.8841.8) and 7 mRNAs (nas-33, math-28, T14B4.19, col-17, rol-6, sqt-1 and irg-4) were potential targets of ginsenoside Rf inhibition of tauopathy. These results partially explain mechanisms underlying ginsenoside Rf-associated alleviation of htau proteotoxicity and will guide future strategies to discover potential therapeutic targets for preventing and alleviating tauopathies.
在病理条件下，人类 tau（htau）过度磷酸化促进了具有神经退行性疾病特征的蛋白毒性细胞内淀粉样聚集物的形成，这些聚集物被称为 tau 病，促使研究人员开发抑制 htau 聚集的治疗方法，这是一种很有前途的治疗策略。人参中的主要活性成分人参皂苷似乎可以抑制 tau 病模型中的 tau 聚集和解离，尽管其活性成分和分子机制尚不清楚。在这里，我们使用了一种新型的秀丽隐杆线虫（C. elegans）tau 病模型来鉴定可能抑制 htau 毒性的人参皂苷单体。我们的研究结果表明，人参皂苷 Rf 可防止 tau 聚集，并逆转异常 tau 聚集诱导的表型和缓解线虫中的神经退行性病变。值得注意的是，对用和未用人参皂苷 Rf 处理的 tau 病线虫进行深度 RNA-seq 分析表明，人参皂苷 Rf 改变了 24 个上调和 36 个下调的长非编码 RNA 转录本、32 个上调和 22 个下调的 miRNA 以及 65 个上调和 30 个下调的 mRNA 转录本的表达水平。基于 GO 和 KEGG 通路注释分析，鉴定出的 mRNAs、miRNAs 和 lncRNAs 相关基因靶点与神经元相关术语（如神经元发育、轴突和运动神经元轴突导向）和长寿调节途径相关。重要的是，RT-qRCR 结果表明，6 个 miRNA（miR-786、miR-2208b、miR-34、miR-241、miR-247 和 miR-4805）、8 个 lncRNA（MSTRG.20812.2、MSTRG.22617.2、MSTRG.28210.13、MSTRG.5728.12、MSTRG.29708.1、MSTRG.3342.25、MSTRG.3342.31 和 MSTRG.8841.8）和 7 个 mRNA（nas-33、math-28、T14B4.19、col-17、rol-6、sqt-1 和 irg-4）是人参皂苷 Rf 抑制 tau 病的潜在靶点。这些结果部分解释了人参皂苷 Rf 缓解 htau 毒性的机制，并将指导未来发现预防和缓解 tau 病的潜在治疗靶点的策略。
