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      Targeting microRNA-134 for seizure control and disease modification in epilepsy

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          Abstract

          MicroRNA-134 is a brain-enriched small noncoding RNA that has been implicated in diverse neuronal functions, including regulating network excitability. Increased expression of microRNA-134 has been reported in several experimental epilepsy models and in resected brain tissue from temporal lobe epilepsy patients. Rodent studies have demonstrated that reducing microRNA-134 expression in the brain using antisense oligonucleotides can increase seizure thresholds and attenuate status epilepticus. Critically, inhibition of microRNA-134 after status epilepticus can potently reduce the occurrence of spontaneous recurrent seizures. Altered plasma levels of microRNA-134 have been reported in epilepsy patients, suggesting microRNA-134 may have diagnostic value as a biomarker. This review summarises findings on the cellular functions of microRNA-134, as well as the preclinical evidence supporting anti-seizure and disease-modifying effects of targeting microRNA-134 in epilepsy. Finally, we draw attention to unanswered questions and some of the challenges and opportunities involved in preclinical development of a microRNA-based oligonucleotide treatment for epilepsy.

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          Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs.

          Lee P. Lim, Nelson C. Lau, Philip Garrett-Engele … (2005)
          MicroRNAs (miRNAs) are a class of noncoding RNAs that post-transcriptionally regulate gene expression in plants and animals. To investigate the influence of miRNAs on transcript levels, we transfected miRNAs into human cells and used microarrays to examine changes in the messenger RNA profile. Here we show that delivering miR-124 causes the expression profile to shift towards that of brain, the organ in which miR-124 is preferentially expressed, whereas delivering miR-1 shifts the profile towards that of muscle, where miR-1 is preferentially expressed. In each case, about 100 messages were downregulated after 12 h. The 3' untranslated regions of these messages had a significant propensity to pair to the 5' region of the miRNA, as expected if many of these messages are the direct targets of the miRNAs. Our results suggest that metazoan miRNAs can reduce the levels of many of their target transcripts, not just the amount of protein deriving from these transcripts. Moreover, miR-1 and miR-124, and presumably other tissue-specific miRNAs, seem to downregulate a far greater number of targets than previously appreciated, thereby helping to define tissue-specific gene expression in humans.
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            Roles for microRNAs in conferring robustness to biological processes.

            Margaret S. Ebert, Phillip A. Sharp (2012)
            Biological systems use a variety of mechanisms to maintain their functions in the face of environmental and genetic perturbations. Increasing evidence suggests that, among their roles as posttranscriptional repressors of gene expression, microRNAs (miRNAs) help to confer robustness to biological processes by reinforcing transcriptional programs and attenuating aberrant transcripts, and they may in some network contexts help suppress random fluctuations in transcript copy number. These activities have important consequences for normal development and physiology, disease, and evolution. Here, we will discuss examples and principles of miRNAs that contribute to robustness in animal systems. Copyright © 2012 Elsevier Inc. All rights reserved.
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              A brain-specific microRNA regulates dendritic spine development.

              Gerhard M Schratt, Fabian Tuebing, Elizabeth Nigh … (2006)
              MicroRNAs are small, non-coding RNAs that control the translation of target messenger RNAs, thereby regulating critical aspects of plant and animal development. In the mammalian nervous system, the spatiotemporal control of mRNA translation has an important role in synaptic development and plasticity. Although a number of microRNAs have been isolated from the mammalian brain, neither the specific microRNAs that regulate synapse function nor their target mRNAs have been identified. Here we show that a brain-specific microRNA, miR-134, is localized to the synapto-dendritic compartment of rat hippocampal neurons and negatively regulates the size of dendritic spines--postsynaptic sites of excitatory synaptic transmission. This effect is mediated by miR-134 inhibition of the translation of an mRNA encoding a protein kinase, Limk1, that controls spine development. Exposure of neurons to extracellular stimuli such as brain-derived neurotrophic factor relieves miR-134 inhibition of Limk1 translation and in this way may contribute to synaptic development, maturation and/or plasticity.
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                Author and article information

                Contributors
                David C. Henshall
                Journal
                Journal ID (nlm-ta): EBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: EBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 09 July 2019
                Publication date Collection: July 2019
                Publication date (Electronic): 09 July 2019
                Volume: 45
                Pages: 646-654
                Affiliations
                [a ]Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
                [b ]FutureNeuro Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland
                Author notes
                [* ]Corresponding author at: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland. dhenshall@ 123456rcsi.ie
                [1]

                Authors contributed equally to the manuscript.

                Article
                Publisher ID: S2352-3964(19)30443-8
                DOI: 10.1016/j.ebiom.2019.07.008
                PMC ID: 6642437
                PubMed ID: 31300345
                SO-VID: 1736a59a-6950-4bc5-aa8d-d42e4310fb88
                Copyright © © 2019 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 14 May 2019
                Date revision received : 3 July 2019
                Date accepted : 3 July 2019
                Categories
                Subject: Review

                Keywords: epileptogenesis,noncoding rna,hippocampal sclerosis,biomarker,rna therapy
                Data availability:
                Keywords: epileptogenesis, noncoding rna, hippocampal sclerosis, biomarker, rna therapy

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