Summary Background Temporal lobe epilepsy is a common and frequently intractable seizure disorder. Its pathogenesis is thought to involve large-scale alterations to the expression of genes ...controlling neurotransmitter signalling, ion channels, synaptic structure, neuronal death, gliosis, and inflammation. Identification of mechanisms coordinating gene networks in patients with temporal lobe epilepsy will help to identify novel therapeutic targets and biomarkers. MicroRNAs (miRNAs) are a family of small non-coding RNAs that control the expression levels of multiple proteins by decreasing mRNA stability and translation, and could therefore be key regulatory mechanisms and therapeutic targets in epilepsy. Recent developments In the past 5 years, studies have found changes in miRNA levels in the hippocampus of patients with temporal lobe epilepsy and in neural tissues from animal models of epilepsy. Early functional studies showed that silencing of brain-specific miR-134 using antisense oligonucleotides (antagomirs) had potent antiseizure effects in animal models, whereas genetic deletion of miR-128 produced fatal epilepsy in mice. Levels of certain miRNAs were also found to be altered in the blood of rodents after seizures. In the past 18 months, functional studies have identified nine novel miRNAs that appear to influence seizures or hippocampal pathology. Their targets include transcription factors, neurotransmitter signalling components, and modulators of neuroinflammation. New approaches to manipulate miRNAs have been tested, including injection of mimics (agomirs) to enhance brain levels of miRNAs. Altered miRNA expression has also been reported in other types of refractory epilepsy and our understanding of how miRNA levels are controlled has grown, with studies on DNA methylation indicating epigenetic regulation. Biofluids (blood) of patients with epilepsy have shown differences in quantity of circulating miRNAs, implying diagnostic biomarker potential. Where next? Recent functional studies need to be replicated to build a robust evidence base. The specific cell types in which miRNAs execute their functions and their primary targets have to be identified, to fully explain the phenotypic effects of modulating miRNAs. Delivery of large molecules such as antisense inhibitors or mimics to the brain poses a challenge, and the multi-targeting effects of miRNAs create additional risks of unanticipated side effects. Potential genetic variation in miRNAs should be explored as the basis for disease susceptibility. The latest findings provide a rich source of new miRNA targets, but substantial challenges remain before their role in the pathogenesis, diagnosis, and treatment of epilepsy can be translated into clinical practice.
This review provides a synthesis of recent profiling studies investigating microRNA (miRNA) changes in experimental and human epilepsy, and outlines mechanistic, therapeutic and diagnostic potentials ...of this research area for clinical practice.
A series of studies in experimental and human epilepsy have undertaken large-scale expression profiling of miRNAs, key regulatory molecules in cells controlling protein levels. Levels of over 100 different miRNAs were found to either increase or decrease in the hippocampus, of which more than 20 were identified in more than one study, including higher levels of miR-23a, miR-34a, miR-132 and miR-146a. Altered levels of enzymes involved in miRNA biogenesis and function, including Dicer and Argonaute 2, have also been found in epileptic brain tissue. Functional studies using oligonucleotide-based inhibitors support roles for miRNAs in the control of cell death, synaptic structure, inflammation and the immune response. Finally, data show brain injuries that precipitate epilepsy generate unique miRNA profiles in biofluids.
miRNA represents a potentially important mechanism controlling protein levels in epilepsy. As such, miRNAs might be targeted to prevent or disrupt epilepsy as well as serve as diagnostic biomarkers of epileptogenesis.
Seizures result from hypersynchronous, abnormal firing of neuronal populations and are the primary clinical symptom of the epilepsies. Brain tissue from animal models and patients with acquired forms ...of epilepsy commonly features selective neuronal loss, gliosis, inflammatory markers and microscopic and macroscopic reorganization of networks. The gene expression landscape is a critical driver of these changes, and gene expression is fine tuned by small, non-coding RNAs called microRNAs (miRNAs). miRNAs inhibit the function of protein-coding transcripts, resulting in changes in multiple aspects of cell structure and function, including axonal and dendritic structure and the repertoire of neurotransmitter receptors, ion channels and transporters that establish neurophysiological functions. Dysregulation of the miRNA system has emerged as a mechanism that underlies epileptogenesis. Given that miRNAs can act on multiple mRNA targets, their manipulation offers a novel, multi-targeting approach to correct disturbed gene expression patterns. Targeting of some miRNAs has also been used to selectively upregulate individual transcripts, offering the possibility of precision therapy approaches for disorders of haploinsufficiency. In this Review, we discuss how miRNAs determine and control neuronal and glial functions, how this process is altered in states associated with hyperexcitability, and the prospects for miRNA targeting for the treatment of epilepsy.
Epilepsy is a common and serious neurological disorder characterised by recurrent spontaneous seizures. Frontline pharmacotherapy includes small-molecule antiseizure drugs that typically target ion ...channels and neurotransmitter systems, but these fail in 30% of patients and do not prevent either the development or progression of epilepsy. An emerging therapeutic target is microRNA (miRNA), small noncoding RNAs that negatively regulate sets of proteins. Their multitargeting action offers unique advantages for certain forms of epilepsy with complex underlying pathophysiology, such as temporal lobe epilepsy (TLE). miRNA can be inhibited by designed antisense oligonucleotides (ASOs; e.g., antimiRs). Here, we outline the prospects for miRNA-based therapies. We review design considerations for nucleic acid-based approaches and the challenges and next steps in developing therapeutic miRNA-targeting molecules for epilepsy.
MicroRNAs are small noncoding RNAs that suppress the translation of mRNAs and have emerged as therapeutic targets in epilepsy and other diseases.Inhibition of certain miRNAs with antisense oligonucleotides (ASOs) is therapeutic in preclinical temporal lobe epilepsy (TLE) models.Chemical modifications can be made to improve the therapeutic properties of ASOs.The blood–brain barrier is an obstacle in delivering ASOs as therapies in neurological disease, and ASOs currently have to be administered by direct central injection.miRNA-targeting ASOs are in clinical trials for other diseases, raising the prospect that they could also be safely applied in epilepsy.
Summary
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.
Epigenetics and Epilepsy Henshall, David C; Kobow, Katja
Cold Spring Harbor perspectives in medicine,
12/2015, Letnik:
5, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Epigenetic processes in the brain involve the transfer of information arising from short-lived cellular signals and changes in neuronal activity into lasting effects on gene expression. Key molecular ...mediators of epigenetics include methylation of DNA, histone modifications, and noncoding RNAs. Emerging findings in animal models and human brain tissue reveal that epilepsy and epileptogenesis are associated with changes to each of these contributors to the epigenome. Understanding and influencing the molecular mechanisms controlling epigenetic change could open new avenues for treatment. DNA methylation, particularly hypermethylation, has been found to increase within gene body regions and interference with DNA methylation in epilepsy can change gene expression profiles and influence epileptogenesis. Posttranscriptional modification of histones, including transient as well as sustained changes to phosphorylation and acetylation, have been reported, which appear to influence gene expression. Finally, roles have emerged for noncoding RNAs in brain excitability and seizure thresholds, including microRNA and long noncoding RNA. Together, research supports strong effects of epigenetics influencing gene expression in epilepsy, suggesting future therapeutic approaches to manipulate epigenetic processes to treat or prevent epilepsy.
Epilepsy is a network disorder driven by fundamental changes in the function of the cells which compose these networks. Driving this aberrant cellular function are large scale changes in gene ...expression and gene expression regulation. Recent studies have revealed rapid and persistent changes in epigenetic control of gene expression as a critical regulator of the epileptic transcriptome.
Epigenetic-mediated gene output regulates many aspects of cellular physiology including neuronal structure, neurotransmitter assembly and abundance, protein abundance of ion channels and other critical neuronal processes. Thus, understanding the contribution of epigenetic-mediated gene regulation could illuminate novel regulatory mechanisms which may form the basis of novel therapeutic approaches to treat epilepsy.
In this review we discuss the effects of epileptogenic brain insults on epigenetic regulation of gene expression, recent efforts to target epigenetic processes to block epileptogenesis and the prospects of an epigenetic-based therapy for epilepsy, and finally we discuss technological advancements which have facilitated the interrogation of the epigenome.
Seizures are bursts of excessive synchronized neuronal activity, suggesting that mechanisms controlling brain excitability are compromised. The voltage-gated potassium channel Kv4.2, a major mediator ...of hyperpolarizing A-type currents in the brain, is a crucial regulator of neuronal excitability. Kv4.2 expression levels are reduced following seizures and in epilepsy, but the underlying mechanisms remain unclear. Here, we report that Kv4.2 mRNA is recruited to the RNA-induced silencing complex shortly after status epilepticus in mice and after kainic acid treatment of hippocampal neurons, coincident with reduction of Kv4.2 protein. We show that the microRNA miR-324-5p inhibits Kv4.2 protein expression and that antagonizing miR-324-5p is neuroprotective and seizure suppressive. MiR-324-5p inhibition also blocks kainic-acid-induced reduction of Kv4.2 protein in vitro and in vivo and delays kainic-acid-induced seizure onset in wild-type but not in Kcnd2 knockout mice. These results reveal an important role for miR-324-5p-mediated silencing of Kv4.2 in seizure onset.
Display omitted
•Kv4.2 mRNA is recruited to the miRNA-induced silencing complex after seizure•Kv4.2 mRNA is a specific target of the microRNA miR-324-5p•Antagonizing miR-324-5p counteracts seizure-induced reduction of Kv4.2 protein•Antagonizing miR-324-5p delays seizure onset in wild-type but not in Kcnd2 KO mice
Gross et al. show that the voltage-gated potassium channel Kv4.2 is regulated by microRNA-induced silencing during seizures. Inhibition of the Kv4.2-targeting microRNA miR-324-5p increases Kv4.2 protein levels, counteracts seizure-induced Kv4.2 downregulation, suppresses kainic-acid-evoked seizures and cell death, and delays seizure onset in wild-type, but not in Kcnd2 knockout mice.
The next generation of etextiles foresees an era of smart wearable garments where embedded seamless intelligence provides the ability to sense, process, and perform. Core to this vision is embedded ...textile functionality enabling dynamic configuration. In this article, we detail a methodology, design, and implementation of a dynamic field-programmable logic-driven fabric soft exosuit. Dynamic field programmability (FP) allows the soft exosuit to alter its functionality and adapt to specific exercise programs depending on the wearers need. The dynamic FP is enabled through motion-based control arm movements of the soft exosuit triggering momentary sensors embedded in the fabric exosuit at specific joint placement points (right arm: wrist and elbow). The embedded circuitry in the fabric exosuit is implemented using a layered and interchangeable approach. This includes logic gate patches (AND, OR, NOT) and a layered textile interconnection panel. This modular and interchangeable design enhances the soft exosuits flexibility and adaptability. A truth table aligning to a rehabilitation healthcare use case was utilized. Tests were completed validating the FP of the soft exosuit and its capability to switch between its embedded logic-driven circuitry and its operational and functionality options controlled by motion movement of the wearers right arm (elbow and wrist). Iterative exercise movement and acceleration-based tests were completed to validate the functionality of the field-programmable logic-driven fabric exosuit. We demonstrate a working soft exosuit prototype with motion-controlled operational functionality that can be applied to rehabilitation applications.
Temporal lobe epilepsy is associated with large-scale, wide-ranging changes in gene expression in the hippocampus. Epigenetic changes to DNA are attractive mechanisms to explain the sustained ...hyperexcitability of chronic epilepsy. Here, through methylation analysis of all annotated C-phosphate-G islands and promoter regions in the human genome, we report a pilot study of the methylation profiles of temporal lobe epilepsy with or without hippocampal sclerosis. Furthermore, by comparative analysis of expression and promoter methylation, we identify methylation sensitive non-coding RNA in human temporal lobe epilepsy. A total of 146 protein-coding genes exhibited altered DNA methylation in temporal lobe epilepsy hippocampus (n = 9) when compared to control (n = 5), with 81.5% of the promoters of these genes displaying hypermethylation. Unique methylation profiles were evident in temporal lobe epilepsy with or without hippocampal sclerosis, in addition to a common methylation profile regardless of pathology grade. Gene ontology terms associated with development, neuron remodelling and neuron maturation were over-represented in the methylation profile of Watson Grade 1 samples (mild hippocampal sclerosis). In addition to genes associated with neuronal, neurotransmitter/synaptic transmission and cell death functions, differential hypermethylation of genes associated with transcriptional regulation was evident in temporal lobe epilepsy, but overall few genes previously associated with epilepsy were among the differentially methylated. Finally, a panel of 13, methylation-sensitive microRNA were identified in temporal lobe epilepsy including MIR27A, miR-193a-5p (MIR193A) and miR-876-3p (MIR876), and the differential methylation of long non-coding RNA documented for the first time. The present study therefore reports select, genome-wide DNA methylation changes in human temporal lobe epilepsy that may contribute to the molecular architecture of the epileptic brain.
PDF
