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- Title
Small molecule regulators of microRNAs identified by high-throughput screen coupled with high-throughput sequencing.
- Authors
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.
- 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. Regulatory miRNAs have significant therapeutic potential. Here the authors developed a screen to identify small molecule drugs that modulate miRNome profiles in human neurons and validated cardiac glycosides as inducers of the neuroprotective miR-132.
- Subjects
SMALL molecules; NUCLEOTIDE sequencing; CARDIAC glycosides; ALZHEIMER'S disease; DRUG discovery
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-43293-0