Abstract
Mesial temporal lobe epilepsy (mTLE) is a chronic neurological disorder characterized by recurrent seizures. The pathogenic mechanisms underlying mTLE may involve defects in the post-transcriptional regulation of gene expression. MicroRNAs (miRNAs) are non-coding RNAs that control the expression of genes at the post-transcriptional level. Here, we performed a genome-wide miRNA profiling study to examine whether miRNA-mediated mechanisms are affected in human mTLE. miRNA profiles of the hippocampus of autopsy control patients and two mTLE patient groups were compared. This revealed segregated miRNA signatures for the three different patient groups and 165 miRNAs with up- or down-regulated expression in mTLE. miRNA in situ hybridization detected cell type-specific changes in miRNA expression and an abnormal nuclear localization of select miRNAs in neurons and glial cells of mTLE patients. Of several cellular processes implicated in mTLE, the immune response was most prominently targeted by deregulated miRNAs. Enhanced expression of inflammatory mediators was paralleled by a reduction in miRNAs that were found to target the 3′-untranslated regions of these genes in reporter assays. miR-221 and miR-222 were shown to regulate endogenous ICAM1 expression and were selectively co-expressed with ICAM1 in astrocytes in mTLE patients. Our findings suggest that miRNA changes in mTLE affect the expression of immunomodulatory proteins thereby further facilitating the immune response. This mechanism may have broad implications given the central role of astrocytes and the immune system in human neurological disease. Overall, this work extends the current concepts of human mTLE pathogenesis to the level of miRNA-mediated gene regulation.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-012-0992-7) contains supplementary material, which is available to authorized users.
Highlights
Temporal lobe epilepsy (TLE) is a neurological condition characterized by recurrent seizures that originate from the temporal lobe
Discrepancies between Mesial temporal lobe epilepsy (mTLE)-associated changes at the mRNA and protein level provide support to the idea that post-transcriptional regulation is affected in mTLE
ICAM1 protein levels are up-regulated in the sclerotic mTLE hippocampus, but this change is not detected at the mRNA level (Fig. 6) [3, 39]
Summary
Temporal lobe epilepsy (TLE) is a neurological condition characterized by recurrent seizures that originate from the temporal lobe. TLE accounts for one-third of all patients with epilepsy [1] and can be divided into several subgroups including mesial TLE (mTLE). MTLE is associated with characteristic pathological features and about 30 % of mTLE patients are pharmaco-resistant [2]. The pathological mechanisms underlying mTLE are poorly understood. Recent studies show that patterns of gene expression are significantly altered in experimental and human mTLE [3,4,5,6,7]. The regulatory mechanisms that normally control gene expression may be affected. Insight into how regulation of gene expression is altered may provide important new insights into mTLE pathogenesis and could yield novel therapeutic targets
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