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

Anne A. Kan, Susan van Erp, Alwin A. H. A. Derijck, Marina de Wit, Ellen V. S. Hessel, Eoghan O'Duibhir, Wilco de Jager, Peter C. Van Rijen, Peter H. Gosselaar, Pierre N. E. de Graan, R. Jeroen Pasterkamp*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)3127-3145
Number of pages19
JournalCellular and Molecular Life Sciences
Volume69
Issue number18
DOIs
Publication statusPublished - Sep 2012

Keywords

  • Mesial temporal lobe epilepsy
  • Nuclear localization
  • Immune regulation
  • Immune system
  • MicroRNA
  • RNA profiling
  • Temporal lobe epilepsy
  • BLOOD-BRAIN-BARRIER
  • NEUROLOGICAL DISORDERS
  • HIPPOCAMPAL SCLEROSIS
  • MESSENGER-RNA
  • T-LYMPHOCYTES
  • EXPRESSION
  • ICAM-1
  • DISEASE
  • EPILEPTOGENESIS
  • ASTROCYTES

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