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Lien Nguyen, PhD




Research Fellow




Postdoctoral Research Fellow




Lien D. Nguyen, Zhiyun Wei, Sergio Barberán-Soler, M. Catarina Silva, Rosalia Rabinovsky, Christina R. Muratore, Jonathan M. S. Stricker, Tracy L. Young-Pearse, Stephen J. Haggarty, and Anna M. Krichevsky

Small Molecule Activators of Neuroprotective microRNAs Identified by High-throughput Screening in Human iPSC-derived Neurons

I am fortunate to have many strong woman role models in my life, from my grandmother, who never had the opportunity to formal education, to various professors who have inspired me to start and continue doing scientific research. My time at Mount Holyoke College, the first of the Seven Sisters, also instills in me a yes-can-do attitude and solidarity with women globally. The Women in Medicine & Science Symposium is a significant opportunity for me to present my research in noncoding RNAs in neurodegeneration, interact with other scientists, and hopefully inspire the next generation of female scientists.

Background. miR-132 is a key miRNA consistently downregulated in Alzheimer’s disease (AD) and various tauopathies. MiR-132 overexpression was shown to rescue neurodegenerative phenotypes in AD animal models. However, upregulating miRNAs through miRNA mimics or virus-mediated gene delivery is limited by poor distribution, low uptake, and high immunogenicity. Therefore, we aimed to discover and validate small molecule drugs that upregulate miR-132.

Methods. We performed a pilot high-throughput miRNA-seq screen of ~2000 drugs in human induced pluripotent stem cell (iPSC)-derived neurons. We obtained the expression profiles of ~500 miRNAs for ~1800 drugs and selected compounds associated with the highest miR-132 expression for validation.

Results. We successfully validated that cardiac glycosides, which are canonical sodium-potassium ATPase inhibitors, upregulated miR-132 at the sub-μM range. The mechanism was increased transcription of the miR-132/212 locus and mimicked by knocking down the major ATPase isoforms in neurons. Treating neurons with sub-μM cardiac glycosides potently downregulated total and phosphorylated tau and protected against cell death by N-methyl-D-aspartate (NMDA), rotenone, and Aβ oligomers.

Conclusions. We identified and validated small molecule drugs that upregulated the neuroprotective miR-132 in neurons. Our dataset also represents a comprehensive resource for discovering small molecule drugs that regulate specific miRNAs for therapeutic purposes.