Manipulating MicroRNAs in Murine Models: Targeting the Multi-Targeting in Epilepsy

Henshall, David C.

doi:10.5698/1535-7511-17.1.43

Cited by 16 publications

(14 citation statements)

References 41 publications

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“…Our unbiased screen for anti-seizure phenotypes identified five antagomirs that protect the brain against prolonged seizures, of which those targeting miR-10a-5p, miR-21a-5p and miR-142a-5p had the most robust effects. This is a substantial addition to the number of miRNAs reported as potential targets for seizure control 20 . It also suggests that many of the upregulated miRNAs in the chronic epilepsy phase may be suppressing targets that would otherwise oppose hyperexcitability.…”

Section: Discussionmentioning

confidence: 94%

“…Spatio-temporal changes to miRNA expression have been reported in the hippocampus following epileptogenic brain injuries and these persist in established epilepsy 17, 18 . In parallel, in vivo deployment of oligonucleotide miRNA inhibitors (antagomirs) has demonstrated functional roles for a few miRNAs in seizure control and epileptogenesis 19, 20 . It remains unknown how many more miRNAs may be suitable targets in epilepsy.…”

Section: Introductionmentioning

confidence: 99%

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Ago2-seq identifies new microRNA targets for seizure control

Reschke

Morris

Connolly

et al. 2019

Preprint

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36MicroRNAs (miRNAs) are short noncoding RNAs that shape the gene expression landscape, 37 including during the pathogenesis of temporal lobe epilepsy (TLE). In order to provide a full 38 catalog of the miRNA changes that happen during experimental TLE, we sequenced 39Argonaute 2-loaded miRNAs in the hippocampus of three different animal models at regular 40 intervals between the time of the initial precipitating insult to the establishment of 41 spontaneous recurrent seizures. The commonly upregulated miRNAs were selected for a 42 functional in vivo screen using oligonucleotide inhibitors. This revealed anti-seizure 43 phenotypes upon inhibition of miR-10a-5p, miR-21a-5p and miR-142a-5p as well as 44 neuroprotection-only effects for inhibition of miR-27a-3p and miR-431-5p. Proteomic data 45 and pathway analysis on predicted and validated targets of these miRNAs indicated a role for 46TGFβ signaling in a shared seizure-modifying mechanism. Together, these results identify 47 functional miRNAs in the hippocampus and a pipeline of new targets for seizure control in 48 epilepsy. 49 50

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Ago2-seq identifies new microRNA targets for seizure control

Reschke

Morris

Connolly

et al. 2019

Preprint

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“…Fourth, experimental studies have shown that manipulating miRNAs can have strong effects on seizures, attendant neuropathology, and epileptogenesis. More than a dozen miRNAs have now been targeted in experimental models and have been reported to produce changes to evoked and spontaneous seizures . Although coexpression of clusters of miRNAs targeting common pathways has been shown during epileptogenesis, some miRNAs may even act individually as master regulators of this phenomenon.…”

Section: Why Micrornas As Molecular Biomarkers Of Epilepsy?mentioning

confidence: 99%

Discovery and validation of blood microRNAs as molecular biomarkers of epilepsy: Ways to close current knowledge gaps

2018

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SummaryThere is a major unmet need for biomarkers of epilepsy. Biofluids such as blood offer a potential source of molecular biomarkers. MicroRNAs (miRNAs) fulfill several key requirements for a blood‐based molecular biomarker being enriched in the brain and dysregulated in epileptic brain tissue, and manipulation of miRNAs can have seizure‐suppressive and disease‐modifying effects in preclinical models. Biofluid miRNAs also possess qualities that are favorable for translation, including stability and easy and cheap assay techniques. Herein we review findings from both clinical and animal models. Studies have featured a mix of unbiased profiling and hypothesis‐driven efforts. Blood levels of several brain‐enriched miRNAs are altered in patients with epilepsy and in patients with drug‐resistant compared to drug‐responsive seizures, with encouraging receiver‐operating characteristic (ROC) curve analyses, both in terms of sensitivity and specificity. Both focal and generalized epilepsies are associated with altered blood miRNA profiles, and associations with clinical parameters including seizure burden have been reported. Results remain preliminary, however. There is a need for continued discovery and validation efforts that include multicenter studies and attention to study design, sample collection methodology, and quality control. Studies focused on epileptogenesis as well as associations with covariables such as sex, etiology, and timing of sampling remain limited. We identify 10 knowledge gaps and propose experiments to close these. If adequately addressed, biofluid miRNAs may be an important future source of diagnostic biomarkers that could also support forthcoming trials of antiepileptogenesis or disease‐modifying therapies.

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“…Extensive research has revealed that microRNAs influence brain structure and function by fine-tuning protein levels of genes involved in neuronal morphology, glial responses, neuroinflammation, and other processes. 12,29 We and our collaborators recently identified a microRNA controlling expression of the Kv4.2 mRNA (KCND2) that encodes a dendritically expressed potassium channel that reduces dendritic excitability. 28 More than a dozen microRNAs have now been identified that positively or negatively affect seizure onset or severity during status epilepticus, status epilepticus-induced brain injury, or development of recurrent spontaneous seizures.…”

Section: Noncoding Rnasmentioning

confidence: 99%

“…28 More than a dozen microRNAs have now been identified that positively or negatively affect seizure onset or severity during status epilepticus, status epilepticus-induced brain injury, or development of recurrent spontaneous seizures. 12,29 We and our collaborators recently identified a microRNA controlling expression of the Kv4.2 mRNA (KCND2) that encodes a dendritically expressed potassium channel that reduces dendritic excitability. 30 Manipulating miR-324 altered surface expression of the potassium channel in neurons, and reducing miR-324 expression rendered mice refractory to status epilepticus, delaying seizure onset and severity and reducing hippocampal damage.…”

Section: Noncoding Rnasmentioning

confidence: 99%

Epigenetic changes in status epilepticus

Henshall

2018

Epilepsia

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Epigenetics refers broadly to processes that influence medium- to long-term expression of genes through changes to the readability and accessibility of the genome to transcription. The mediators include DNA methylation, posttranslational modification of histone proteins, and noncoding RNAs. The present review focuses on recent findings showing epigenetic processes influence susceptibility to and severity of status epilepticus, while status epilepticus in turn drives changes to epigenetic marks that affect the gene expression landscape underlying epileptogenesis. Experimental status epilepticus triggers select, spatiotemporal hypo- and hypermethylation changes throughout the genome. Experimental manipulations that alter DNA methylation after status epilepticus are associated with amelioration of cognitive and hyperexcitability phenotypes. Prolonged seizures also modify chromatin compaction via acetylation and other changes to histones and their expression. Finally, short noncoding RNAs called microRNAs target networks of genes through posttranscriptional and other mechanisms and their modulation can alter status epilepticus as well as serve as potential molecular biomarkers. Long noncoding RNAs have also been targeted to influence expression of genes affecting electrophysiological functions of neurons. In summary, epigenetic processes can modulate status epilepticus, and status epilepticus imposes changes on the epigenome, which together provide novel insight into pathomechanisms, therapy, and biomarkers for status epilepticus.

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Manipulating MicroRNAs in Murine Models: Targeting the Multi-Targeting in Epilepsy

Cited by 16 publications

References 41 publications

Ago2-seq identifies new microRNA targets for seizure control

Ago2-seq identifies new microRNA targets for seizure control

Discovery and validation of blood microRNAs as molecular biomarkers of epilepsy: Ways to close current knowledge gaps

Epigenetic changes in status epilepticus

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