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

Morten Trillingsgaard Venø; Cristina Ruedell Reschke; Gareth Morris; Niamh M. C. Connolly; Junyi Su; Yan Yan; Tobías Engel; Eva Maria Jimenez-Mateos; Lea Mørch Harder; Dennis Pultz; Stefan J. Haunsberger; Ajay Pal; Braxton A. Norwood; Lara S. Costard; Valentin Neubert; Federico Del Gallo; Beatrice Salvetti; Vamshidhar R. Vangoor; Amaya Sanz‐Rodriguez; Juha Muilu; Paolo Francesco Fabene; R. Jeroen Pasterkamp; Jochen H.M. Prehn; Stéphanie Schorge; Jens Andersen; Felix Rosenow; Sebastian Bauer; Jørgen Kjems; David Clifford Henshall

doi:10.1101/777144

NeurosciencebioRxivSep 24, 2019

Preprint

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

Morten Trillingsgaard Venø iD, Cristina Ruedell Reschke iD, Gareth Morris iD, Niamh M. C. Connolly iD, Junyi Su, Yan Yan iD, Tobías Engel iD, Eva Maria Jimenez-Mateos iD, Lea Mørch Harder iD, Dennis Pultz, Stefan J. Haunsberger iD, Ajay Pal iD, Braxton A. Norwood, Lara S. Costard iD, Valentin Neubert iD, Federico Del Gallo iD, Beatrice Salvetti, Vamshidhar R. Vangoor iD, Amaya Sanz‐Rodriguez, Juha Muilu iD, Paolo Francesco Fabene iD, R. Jeroen Pasterkamp iD, Jochen H.M. Prehn iD, Stéphanie Schorge iD, Jens Andersen iD, , David Clifford Henshall iD

Abstract

MicroRNAs (miRNAs) are short noncoding RNAs that shape the gene expression landscape, including during the pathogenesis of temporal lobe epilepsy (TLE). In order to provide a full catalog of the miRNA changes that happen during experimental TLE, we sequenced Argonaute 2-loaded miRNAs in the hippocampus of three different animal models at regular intervals between the time of the initial precipitating insult to the establishment of spontaneous recurrent seizures. The commonly upregulated miRNAs were selected for a functional in vivo screen using oligonucleotide inhibitors. This revealed anti-seizure phenotypes upon inhibition of miR-10a-5p, miR-21a-5p and miR-142a-5p as well as neuroprotection-only effects for inhibition of miR-27a-3p and miR-431-5p. Proteomic data and pathway analysis on predicted and validated targets of these miRNAs indicated a role for TGF{beta} signaling in a shared seizure-modifying mechanism. Together, these results identify functional miRNAs in the hippocampus and a pipeline of new targets for seizure control in epilepsy.

PDF DOI