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

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  • Morten T. Venø
  • ,
  • Cristina R. Reschke, Royal College of Surgeons in Ireland
  • ,
  • Gareth Morris, Royal College of Surgeons in Ireland, University College London
  • ,
  • Niamh M.C. Connolly, Royal College of Surgeons in Ireland
  • ,
  • Junyi Su
  • Yan Yan
  • Tobias Engel, Royal College of Surgeons in Ireland
  • ,
  • Eva M. Jimenez-Mateos, Royal College of Surgeons in Ireland
  • ,
  • Lea M. Harder, Syddansk Universitet
  • ,
  • Dennis Pultz, Syddansk Universitet
  • ,
  • Stefan J. Haunsberger, Royal College of Surgeons in Ireland
  • ,
  • Ajay Pal, Royal College of Surgeons in Ireland
  • ,
  • Janosch P. Heller, Royal College of Surgeons in Ireland, University College London
  • ,
  • Aoife Campbell, Royal College of Surgeons in Ireland
  • ,
  • Elena Langa, Royal College of Surgeons in Ireland
  • ,
  • Gary P. Brennan, Royal College of Surgeons in Ireland
  • ,
  • Karen Conboy, Royal College of Surgeons in Ireland
  • ,
  • Amy Richardson, University College London
  • ,
  • Braxton A. Norwood, Expesicor Inc, Diagnostics Development
  • ,
  • Lara S. Costard, University of Marburg, Goethe University Frankfurt
  • ,
  • Valentin Neubert, University of Marburg, University of Rostock
  • ,
  • Federico Del Gallo, University of Verona
  • ,
  • Beatrice Salvetti, University of Verona
  • ,
  • Vamshidhar R. Vangoor, Utrecht University
  • ,
  • Amaya Sanz-Rodriguez, Royal College of Surgeons in Ireland
  • ,
  • Juha Muilu, Research and Development
  • ,
  • Paolo F. Fabene, University of Verona
  • ,
  • R. Jeroen Pasterkamp, Utrecht University
  • ,
  • Jochen H.M. Prehn, Royal College of Surgeons in Ireland
  • ,
  • Stephanie Schorge, University College London
  • ,
  • Jens S. Andersen, Syddansk Universitet
  • ,
  • Felix Rosenow, University of Marburg, Goethe University Frankfurt
  • ,
  • Sebastian Bauer, University of Marburg, Goethe University Frankfurt
  • ,
  • Jørgen Kjems
  • David C. Henshall, Royal College of Surgeons in Ireland

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.

OriginalsprogEngelsk
TidsskriftProceedings of the National Academy of Sciences of the United States of America
Vol/bind117
Nummer27
Sider (fra-til)15977-15988
Antal sider12
ISSN0027-8424
DOI
StatusUdgivet - jul. 2020

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