Epilepsy and microRNA

Abstract

MicroRNA (miRNA) is a class of small non-coding RNA which regulates post-transcriptional gene expression by repressing and thereby fine-tuning protein production, mainly via sequence-specific binding within the 3'untranslated region of mRNA transcripts. Although in humans there are only ∼1600 miRNAs, bioinformatics, systems studies and advanced quantitative proteomics reveal miRNA regulation of over half of all protein-coding genes and that each miRNA can regulate multiple proteins. Epilepsy is a common, serious neurologic disorder characterized by recurring unprovoked seizures that result from abnormal firing of populations of neurons in the brain. The brain expresses several unique miRNAs which control dendritic morphology as well as ion channel levels, neuronal migration and glial function. There is an emerging view that the patho-mechanisms underlying the process of epileptogenesis, as well as maintenance and progression of the epileptic state, involve miRNAs that control multiple genes and proteins on a systems level. Expression profiling studies reveal select changes to brain miRNA levels following prolonged seizures (status epilepticus) in animal models. Inflammation, stress signaling and neuronal excitation are among the pathways most impacted. Analysis of miRNA expression in human epilepsy has also been performed, where again neuroinflammatory processes were prominent. These studies suggest that miRNAs may regulate certain key processes but are not necessarily broadly altering all patho-mechanisms in epilepsy. Functional studies employing antagomirs have identified contributions from miR-34a and miR-132 to seizure-induced neuronal death whereas silencing miR-134 potently reduced status epilepticus, seizure-damage and the later occurrence of spontaneous seizures. Efforts to identify the in vivo target(s) of epilepsy-regulated miRNAs, is now a priority. Last, miRNAs are stable, information-carrying (paracrine) signals. Profiling miRNA in biofluids may represent a novel source of disease biomarkers in epilepsy. In summary, miRNA is emerging as a critical new layer of gene expression control with implications for the cause and treatment of epilepsy.