Antagonizing increased miR-135a levels at the chronic stage of.....pdf (4.33 MB)

Antagonizing increased miR-135a levels at the chronic stage of experimental TLE reduces spontaneous recurrent seizures

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journal contribution
posted on 10.09.2021, 14:06 by Vamshidhar R Vangoor, Cristina Ruedell ReschkeCristina Ruedell Reschke, Ketharini Senthilkumar, Lieke L Van De Haar, Marina De Wit, Giuliano Giuliani, Mark H Broekhoven, Gareth MorrisGareth Morris, Tobias EngelTobias Engel, Gary Brennan, Ronan Conroy, Peter C Van Rijen, Peter H Gosselaar, Stephanie Schorge, Roel QJ Schaapveld, David HenshallDavid Henshall, Pierre N E De Graan, R Jeroen Pasterkamp

Mesial Temporal Lobe Epilepsy (mTLE) is a chronic neurological disease characterized by 54 recurrent seizures. The anti-epileptic drugs currently available to treat mTLE are ineffective 55 in one-third of patients and lack disease-modifying effects. MicroRNAs (miRNAs), a class of 56 small non-coding RNAs which control gene expression at the post-transcriptional level, play 57 a key role in the pathogenesis of mTLE and other epilepsies. Although manipulation of 58 miRNAs at acute stages has been reported to reduce subsequent spontaneous seizures, it is 59 uncertain whether targeting miRNAs at chronic stages of mTLE can also reduce seizures. 60 Furthermore, the functional role and downstream targets of most epilepsy-associated 61 miRNAs remain poorly understood. Here, we show that miR-135a is selectively upregulated 62 within neurons in epileptic brain and report that targeting miR-135a in vivo using antagomirs 63 after onset of spontaneous recurrent seizures can reduce seizure activity at the chronic stage 64 of experimental mTLE in male mice. Further, by using an unbiased approach combining 65 immunoprecipitation and RNA sequencing, we identify several novel neuronal targets of 66 miR-135a, including Mef2a. Mef2 proteins are key regulators of excitatory synapse density. 67 Mef2a and miR-135a show reciprocal expression regulation in human (of both sexes) and 68 experimental TLE, and miR-135a regulates dendritic spine number and type through Mef2. 69 Together, our data show that miR-135a is target for reducing seizure activity in chronic 70 epilepsy, and that deregulation of miR-135a in epilepsy may alter Mef2a expression and 71 thereby affect synaptic function and plasticity

Funding

European Union’s 7th Framework Programme Grant Agreement 602130

EpimiRNA

Dutch Epilepsiefonds (WAR 12-08, 15-05)

Netherlands Organization for Scientific Research (ALW-VICI)

History

Comments

The original article is available at https://www.jneurosci.org

Published Citation

Vangoor VR. et al. Antagonizing increased miR-135a levels at the chronic stage of experimeintal TLE reduces spontaneous recurrent seizures. J Neurosci. 2019;39(26):5064-5079.

Publication Date

26 June 2019

PubMed ID

31015341

Department/Unit

  • FutureNeuro Centre
  • Physiology and Medical Physics
  • Public Health and Epidemiology

Research Area

  • Population Health and Health Services
  • Neurological and Psychiatric Disorders
  • Health Professions Education
  • Cancer

Publisher

Society for Neuroscience

Version

  • Accepted Version (Postprint)