MicroRNA and epilepsy: profiling, functions and potential clinical applications

Abstract

Purpose of review: 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.

Recent findings: 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.

Summary: 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.

Figure 1. How microRNAs work

(A) Simplified concept of how miRNAs work. The normal translation of a messenger RNA (mRNA) into protein can be reduced by miRNA binding. Protein depicted is a surface representation of human Ago-2 (with permission from Schirle et al (2012) [2]). (B) Cannonical pathway for production of mature miRNAs. Transcription by pol II or III produces a primary transcript before two stages of processing that results in production of the mature miRNA. Scheme is a simplification of the process. Drosha refers to the microprocessor complex which comprises several other proteins including DGCR8 and RNA-associated proteins. (C) Mechanism by which miRNAs target mRNAs. MiRNA are up-loaded to the RISC complex which contains Ago-2. Targeting of the miRNA to the mRNA usually occurs within the 3′ untranslated region, and features a “seed” region of 7-8 nt, followed by additional binding. The result is degradation of the mRNA or translation inhibition. MiRNAs also function in non-RISC related processing, for example acting as “decoys”. The miRNA sequence in C is mmu-miR-34a-5p.

Figure 2. Conserved brain and blood miRNA responses following epileptogenic brain injuries

(A) Profiling data show unique as well as common up- and down-regulated miRNAs 24 h after different epileptogenic insults to the brain. (B) Blood profiling data show each insult produces unique as well as shared miRNA expression responses in blood suggesting a set of common miRNAs that could represent biomarkers of epileptogenic brain injury. Boxes list the conserved miRNAs. Note, -3p and -5p denote mature miRNAs that originate from opposite arms of the same miRNA. Data are adapted with permission from Liu et al. [••17].