A systems approach delivers a functional microRNA catalog and expanded targets for seizure suppression in temporal lobe epilepsy

Morten T Venø, Cristina R Reschke, Gareth Morris, Niamh M C Connolly, Junyi Su, Yan Yan, Tobias Engel, Eva M Jimenez-Mateos, Lea M Harder, Dennis Pultz, Stefan J Haunsberger, Ajay Pal, Janosch P Heller, Aoife Campbell, Elena Langa, Gary P Brennan, Karen Conboy, Amy Richardson, Braxton A Norwood, Lara S CostardValentin Neubert, Federico Del Gallo, Beatrice Salvetti, Vamshidhar R Vangoor, Amaya Sanz-Rodriguez, Juha Muilu, Paolo F Fabene, R Jeroen Pasterkamp, Jochen H M Prehn, Stephanie Schorge, Jens S Andersen, Felix Rosenow, Sebastian Bauer, Jørgen Kjems, David C Henshall

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Temporal lobe epilepsy is the most common drug-resistant form of epilepsy in adults. The reorganization of neural networks and the gene expression landscape underlying pathophysiologic network behavior in brain structures such as the hippocampus has been suggested to be controlled, in part, by microRNAs. To systematically assess their significance, we sequenced Argonaute-loaded microRNAs to define functionally engaged microRNAs in the hippocampus of three different animal models in two species and at six time points between the initial precipitating insult through to the establishment of chronic epilepsy. We then selected commonly up-regulated microRNAs for a functional in vivo therapeutic screen using oligonucleotide inhibitors. Argonaute sequencing generated 1.44 billion small RNA reads of which up to 82% were microRNAs, with over 400 unique microRNAs detected per model. Approximately half of the detected microRNAs were dysregulated in each epilepsy model. We prioritized commonly up-regulated microRNAs that were fully conserved in humans and designed custom antisense oligonucleotides for these candidate targets. Antiseizure phenotypes were observed upon knockdown of miR-10a-5p, miR-21a-5p, and miR-142a-5p and electrophysiological analyses indicated broad safety of this approach. Combined inhibition of these three microRNAs reduced spontaneous seizures in epileptic mice. Proteomic data, RNA sequencing, and pathway analysis on predicted and validated targets of these microRNAs implicated derepressed TGF-β signaling as a shared seizure-modifying mechanism. Correspondingly, inhibition of TGF-β signaling occluded the antiseizure effects of the antagomirs. Together, these results identify shared, dysregulated, and functionally active microRNAs during the pathogenesis of epilepsy which represent therapeutic antiseizure targets.

Original languageEnglish
Article number27
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number27
Pages (from-to)15977-15988
ISSN0027-8424
DOIs
Publication statusPublished - 7. Jul 2020

Keywords

  • Antisense oligonucleotide
  • Biomarker
  • Epigenetic
  • Epilepsy
  • Noncoding RNA

Fingerprint Dive into the research topics of 'A systems approach delivers a functional microRNA catalog and expanded targets for seizure suppression in temporal lobe epilepsy'. Together they form a unique fingerprint.

  • Cite this

    Venø, M. T., Reschke, C. R., Morris, G., Connolly, N. M. C., Su, J., Yan, Y., Engel, T., Jimenez-Mateos, E. M., Harder, L. M., Pultz, D., Haunsberger, S. J., Pal, A., Heller, J. P., Campbell, A., Langa, E., Brennan, G. P., Conboy, K., Richardson, A., Norwood, B. A., ... Henshall, D. C. (2020). A systems approach delivers a functional microRNA catalog and expanded targets for seizure suppression in temporal lobe epilepsy. Proceedings of the National Academy of Sciences of the United States of America, 117(27), 15977-15988. [27]. https://doi.org/10.1073/pnas.1919313117