Small molecule regulators of microRNAs identified by high-throughput screen coupled with high-throughput sequencing

Lien D. Nguyen, Zhiyun Wei (), M. Catarina Silva, Sergio Barberán-Soler, Jiarui Zhang, Rosalia Rabinovsky, Christina R. Muratore, Jonathan M. S. Stricker, Colin Hortman, Tracy L. Young-Pearse, Stephen J. Haggarty and Anna M. Krichevsky ()
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Lien D. Nguyen: Brigham and Women’s Hospital and Harvard Medical School
Zhiyun Wei: Brigham and Women’s Hospital and Harvard Medical School
M. Catarina Silva: Massachusetts General Hospital and Harvard Medical School
Sergio Barberán-Soler: RealSeq Biosciences
Jiarui Zhang: Boston University School of Medicine
Rosalia Rabinovsky: Brigham and Women’s Hospital and Harvard Medical School
Christina R. Muratore: Brigham and Women’s Hospital and Harvard Medical School
Jonathan M. S. Stricker: Brigham and Women’s Hospital and Harvard Medical School
Colin Hortman: RealSeq Biosciences
Tracy L. Young-Pearse: Brigham and Women’s Hospital and Harvard Medical School
Stephen J. Haggarty: Massachusetts General Hospital and Harvard Medical School
Anna M. Krichevsky: Brigham and Women’s Hospital and Harvard Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract MicroRNAs (miRNAs) regulate fundamental biological processes by silencing mRNA targets and are dysregulated in many diseases. Therefore, miRNA replacement or inhibition can be harnessed as potential therapeutics. However, existing strategies for miRNA modulation using oligonucleotides and gene therapies are challenging, especially for neurological diseases, and none have yet gained clinical approval. We explore a different approach by screening a biodiverse library of small molecule compounds for their ability to modulate hundreds of miRNAs in human induced pluripotent stem cell-derived neurons. We demonstrate the utility of the screen by identifying cardiac glycosides as potent inducers of miR-132, a key neuroprotective miRNA downregulated in Alzheimer’s disease and other tauopathies. Coordinately, cardiac glycosides downregulate known miR-132 targets, including Tau, and protect rodent and human neurons against various toxic insults. More generally, our dataset of 1370 drug-like compounds and their effects on the miRNome provides a valuable resource for further miRNA-based drug discovery.

Date: 2023
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DOI: 10.1038/s41467-023-43293-0

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