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Genome-wide microRNA profiling of human temporal lobe epilepsy identifies modulators of the immune response.

TitleGenome-wide microRNA profiling of human temporal lobe epilepsy identifies modulators of the immune response.
Publication TypeJournal Article
Year of Publication2012
AuthorsKan AA, van Erp S, Derijck AAHA, de Wit M, Hessel EVS, O'Duibhir E, de Jager W, Van Rijen PC, Gosselaar PH, de Graan PNE, R Pasterkamp J
JournalCell Mol Life Sci
Date Published2012 Sep
KeywordsAdult, Aged, Aged, 80 and over, Astrocytes, Base Sequence, Case-Control Studies, Epilepsy, Temporal Lobe, Female, Gene Expression Profiling, Genes, MHC Class II, Genome, Human, Hippocampus, Humans, Inflammation Mediators, Male, MicroRNAs, Middle Aged, Molecular Sequence Data, Neuroglia, Neurons

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.

Alternate JournalCell. Mol. Life Sci.
PubMed ID22535415
PubMed Central IDPMC3428527
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