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.
Show 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.
Matching journals
The top 12 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Loss of function of the mitochondrial peptidase PITRM1 induces proteotoxic stress and Alzheimer's disease-like pathology in human cerebral organoids 93%
- Alzheimer's Disease Patient Brain Extracts Induce Multiple Pathologies in Vascularized Neuroimmune Organoids for Disease Modeling and Drug Discovery 92%
- Integrative transcriptomics and electrophysiological profiling of hiPSC-derived neurons identifies novel druggable pathways in Koolen-de Vries Syndrome 92%
Similar papers in this journal
- SSRI antidepressant citalopram reverses the Warburg effect to inhibit hepatocellular carcinoma by directly targeting GLUT1 93%
- The Glycolytic Metabolite Methylglyoxal Covalently Inactivates the NLRP3 Inflammasome. 92%
- Structure-based Design of CDC42 Effector Interaction Inhibitors For the Treatment of Cancer 92%
Similar papers in this journal
- The Endo-GeneScreen Platform Identifies Drug-Like Probes that Regulate Endogenous Protein Levels within Physiological Contexts 94%
- Machine Learning Identifies Novel Candidates for DrugRepurposing in Alzheimer's Disease 94%
- Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.