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

Autor: Cristina R. Reschke, Junyi Su, Lara S. Costard, R. Jeroen Pasterkamp, Vamshidhar R. Vangoor, Gary P. Brennan, Federico Del Gallo, Tobias Engel, Valentin Neubert, Jochen H. M. Prehn, Aoife Campbell, Dennis Pultz, Lea M. Harder, Janosch P. Heller, Morten T. Venø, Yan Yan, David C. Henshall, Braxton A. Norwood, Jørgen Kjems, Niamh M. C. Connolly, Gareth Morris, Jens S. Andersen, Amaya Sanz-Rodriguez, Elena Langa, Stephanie Schorge, Felix Rosenow, Ajay Pal, Beatrice Salvetti, Karen Conboy, Juha Muilu, Paolo F. Fabene, Sebastian Bauer, Eva M. Jimenez-Mateos, Stefan J. Haunsberger, Amy Richardson
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: 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, Costard, L S, Neubert, V, Gallo, F D, Salvetti, B, Vangoor, V R, Sanz-Rodriguez, A, Muilu, J, Fabene, P F, Pasterkamp, R J, Prehn, J H M, Schorge, S, Andersen, J S, Rosenow, F, Bauer, S, Kjems, J & 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, vol. 117, no. 27, pp. 15977-15988 . https://doi.org/10.1073/pnas.1919313117
Proceedings of the National Academy of Sciences
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, Costard, L S, Neubert, V, Del Gallo, F, Salvetti, B, Vangoor, V R, Sanz-Rodriguez, A, Muilu, J, Fabene, P F, Pasterkamp, R J, Prehn, J H M, Schorge, S, Andersen, J S, Rosenow, F, Bauer, S, Kjems, J & 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, vol. 117, no. 27, 27, pp. 15977-15988 . https://doi.org/10.1073/pnas.1919313117
Proceedings of the National Academy of Sciences of the United States of America
Popis: Significance Temporal lobe epilepsy is commonly drug resistant and is associated with dysregulated hippocampal gene expression. MicroRNAs are short noncoding RNAs which control protein levels by binding target mRNAs via Argonaute proteins. We sequenced Argonaute-bound microRNAs from the hippocampus of three rodent epilepsy models, identifying common and unique functioning microRNAs at each stage of epileptogenesis. We designed oligonucleotide inhibitors against six microRNAs shared among models in chronic epilepsy and show three of these protected against acute and spontaneous seizures in a mouse model. We demonstrate that normal brain physiology is not obviously disrupted by these treatments and used a multiomics approach to identify a common mechanistic pathway for the therapeutic protective effects. Overall, these studies reveal potential treatments for drug-resistant epilepsy.
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.
Databáze: OpenAIRE
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