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

Nguyen, Lien D., Wei, Zhiyun, Silva, M. Catarina, Barberán-Soler, Sergio, Zhang, Jiarui, Rabinovsky, Rosalia, Muratore, Christina R., Stricker, Jonathan M. S., Hortman, Colin, Young-Pearse, Tracy L., Haggarty, Stephen J., Krichevsky, Anna M.·2023·Nature Communications
DOI 10.1038/s41467-023-43293-0PMC PMC10663445

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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.

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Metadata

Authors
Nguyen, L. D., Wei, Z., Silva, M. C., Barberán-Soler, S., Zhang, J., Rabinovsky, R., Muratore, C. R., Stricker, J. M. S., Hortman, C., Young-Pearse, T. L., Haggarty, S. J., & Krichevsky, A. M.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-11-21
Volume
14
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-023-43293-0
PMC
PMC10663445
Cited by
50
References
7
Language
en
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