Ginsenoside Rf inhibits human tau proteotoxicity and causes specific LncRNA, miRNA and mRNA expression changes in Caenorhabditis elegans model of tauopathy

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.