title: Increased reelin promoter methylation is associated with granule cell dispersion in human temporal lobe epilepsy.
abstract: Mesial temporal sclerosis (MTS) is the most common lesion in chronic, intractable temporal lobe epilepsies (TLE) and characterized by segmental neuronal cell loss in major hippocampal segments. Another histopathological hallmark includes granule cell dispersion (GCD), an architectural disturbance of the dentate gyrus encountered in approximately 50% of patients with mesial temporal sclerosis. Reelin, which plays a key role during hippocampal development and maintenance of laminar organization, is synthesized and released by Cajal-Retzius cells of the dentate molecular layer, and previous studies have shown that Reelin transcript levels are downregulated in human temporal lobe epilepsies specimens. To investigate whether epigenetic silencing by Reelin promoter methylation may be an underlying pathogenetic mechanism of GCD, DNA was harvested from 3 microdissected hippocampal subregions (i.e. molecular and granule cell layers of the dentate gyrus and presubiculum) from 8 MTS specimens with GCD, 5 TLE samples without GCD, and 3 autopsy controls. Promoter methylation was analyzed after bisulfite treatment, cloning, and direct sequencing; immunohistochemistry was performed to identify Cajal-Retzius cells. Reelin promoter methylation was found to be greater in TLE specimens than in controls; promoter methylation correlated with GCD among TLE specimens (p < 0.0002). No other clinical or histopathological parameter (i.e. sex, age, seizure duration, medication or extent, of MTS) correlated with promoter methylation. These data support a compromised Reelin-signaling pathway and identify promoter methylation as an epigenetic mechanism in the pathogenesis of TLE.
authors.affiliation: Institute of Neuropathology, University Medical School Erlangen, Erlangen, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Kobow
authors.forename: Ina
authors.initials: I
authors.lastname: Jeske
authors.forename: Michelle
authors.initials: M
authors.lastname: Hildebrandt
authors.forename: Jan
authors.initials: J
authors.lastname: Hauke
authors.forename: Eric
authors.initials: E
authors.lastname: Hahnen
authors.forename: Rolf
authors.initials: R
authors.lastname: Buslei
authors.forename: Michael
authors.initials: M
authors.lastname: Buchfelder
authors.forename: Daniel
authors.initials: D
authors.lastname: Weigel
authors.forename: Hermann
authors.initials: H
authors.lastname: Stefan
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kasper
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Pauli
authors.forename: Ingmar
authors.initials: I
authors.lastname: Blümcke
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D064032:Calbindin 2; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics* / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D016009:Chi-Square Distribution; D019175:DNA Methylation / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004833:Epilepsy, Temporal Lobe / Q000473:pathology*; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D000091042:Reelin Protein; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D064032:Calbindin 2; D015816:Cell Adhesion Molecules, Neuronal; D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000091042:Reelin Protein; D064030:S100 Calcium Binding Protein G; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C000717127:RELN protein, human; D012697:Serine Endopeptidases