Small Molecule Inducers of Neuroprotective miR-132 Identified by HTS-HTS in Human iPSC-derived Neurons

Nguyen, L. D.; Wei, Z.; Silva, M. C.; Barberan-Soler, S.; Rabinovsky, R.; Muratore, C. R.; Stricker, J. M. S.; Hortman, C.; Young-Pearse, T. L.; Haggarty, S. J.; Krichevsky, A. M.

doi:10.1101/2022.11.01.514550

bioRxiv · 10.1101/2022.11.01.514550

Small Molecule Inducers of Neuroprotective miR-132 Identified by HTS-HTS in Human iPSC-derived Neurons

Nguyen, L. D.·Wei, Z.·Silva, M. C.·Barberan-Soler, S.·Rabinovsky, R.·Muratore, C. R.·Stricker, J. M. S.·Hortman, C.·Young-Pearse, T. L.·Haggarty, S. J.·Krichevsky, A. M.

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Abstract

MicroRNAs (miRNAs) are short RNAs that regulate fundamental biological processes. miR-132, a key miRNA with established functions in Tau homeostasis and neuroprotection, is consistently downregulated in Alzheimers disease (AD) and other tauopathies. miR-132 overexpression rescues neurodegenerative phenotypes in several AD models. To complement research on miRNA-mimicking oligonucleotides targeting the central nervous system, we developed a high-throughput-screen coupled high-throughput-sequencing (HTS-HTS) in human induced pluripotent stem cell (iPSC)-derived neurons to identify small molecule inducers of miR-132. We discovered that cardiac glycosides, which are canonical sodium-potassium ATPase inhibitors, selectively upregulated miR-132 in the sub-M range. Coordinately, cardiac glycoside treatment downregulated total and phosphorylated Tau in rodent and human neurons and protected against toxicity by glutamate, N-methyl-D-aspartate, rotenone, and A{beta} oligomers. In conclusion, we identified small-molecule drugs that upregulated the neuroprotective miR-132 and ameliorated neurodegenerative phenotypes. Our dataset also represents a comprehensive resource for discovering small molecules that modulate specific miRNAs for therapeutic purposes.

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Nguyen, L. D., Wei, Z., Silva, M. C., Barberan-Soler, S., Rabinovsky, R., Muratore, C. R., Stricker, J. M. S., Hortman, C., Young-Pearse, T. L., Haggarty, S. J., Krichevsky, A. M.. 2022-11-01. Small Molecule Inducers of Neuroprotective miR-132 Identified by HTS-HTS in Human iPSC-derived Neurons. https://doi.org/10.1101/2022.11.01.514550

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