Dataset Information

Differential expression of miR-184 in temporal lobe epilepsy patients with and without hippocampal sclerosis - Influence on microglial function.

ABSTRACT: Epilepsy is one of the most common neurological disorders characterized by recurrent seizures due to neuronal hyperexcitability. Here we compared miRNA expression patterns in mesial temporal lobe epilepsy with and without hippocampal sclerosis (mTLE?+?HS and mTLE -HS) to investigate the regulatory mechanisms differentiating both patient groups. Whole genome miRNA sequencing in surgically resected hippocampi did not reveal obvious differences in expression profiles between the two groups of patients. However, one microRNA (miR-184) was significantly dysregulated, which was confirmed by qPCR. We observed that overexpression of miR-184 inhibited cytokine release after LPS stimulation in primary microglial cells, while it did not affect the viability of murine primary neurons and primary astrocytes. Pathway analysis revealed that miR-184 is potentially involved in the regulation of inflammatory signal transduction and apoptosis. Dysregulation of some the potential miR-184 target genes was confirmed by qPCR and 3'UTR luciferase reporter assay. The reduced expression of miR-184 observed in patients with mTLE?+?HS together with its anti-inflammatory effects indicate that miR-184 might be involved in the modulation of inflammatory processes associated with hippocampal sclerosis which warrants further studies elucidating the role of miR-184 in the pathophysiology of mTLE.

SUBMITTER: Danis B

PROVIDER: S-EPMC5036198 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Differential expression of miR-184 in temporal lobe epilepsy patients with and without hippocampal sclerosis - Influence on microglial function.

Danis Bénédicte B van Rikxoort Marijke M Kretschmann Anita A Zhang Jiong J Godard Patrice P Andonovic Lidija L Siegel Franziska F Niehusmann Pitt P Hanon Etienne E Delev Daniel D von Lehe Marec M Kaminski Rafal M RM Pfeifer Alexander A Foerch Patrik P

Scientific reports 20160926

Epilepsy is one of the most common neurological disorders characterized by recurrent seizures due to neuronal hyperexcitability. Here we compared miRNA expression patterns in mesial temporal lobe epilepsy with and without hippocampal sclerosis (mTLE + HS and mTLE -HS) to investigate the regulatory mechanisms differentiating both patient groups. Whole genome miRNA sequencing in surgically resected hippocampi did not reveal obvious differences in expression profiles between the two groups of patie ...[more]

PMID: 27666871

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Project description:ObjectiveHippocampal sclerosis is the most common neuropathologic finding in cases of medically intractable mesial temporal lobe epilepsy. In this study, we analyzed the gene expression profiles of dentate granule cells of patients with mesial temporal lobe epilepsy with and without hippocampal sclerosis to show that next-generation sequencing methods can produce interpretable genomic data from RNA collected from small homogenous cell populations, and to shed light on the transcriptional changes associated with hippocampal sclerosis.MethodsRNA was extracted, and complementary DNA (cDNA) was prepared and amplified from dentate granule cells that had been harvested by laser capture microdissection from surgically resected hippocampi from patients with mesial temporal lobe epilepsy with and without hippocampal sclerosis. Sequencing libraries were sequenced, and the resulting sequencing reads were aligned to the reference genome. Differential expression analysis was used to ascertain expression differences between patients with and without hippocampal sclerosis.ResultsGreater than 90% of the RNA-Seq reads aligned to the reference. There was high concordance between transcriptional profiles obtained for duplicate samples. Principal component analysis revealed that the presence or absence of hippocampal sclerosis was the main determinant of the variance within the data. Among the genes up-regulated in the hippocampal sclerosis samples, there was significant enrichment for genes involved in oxidative phosphorylation.SignificanceBy analyzing the gene expression profiles of dentate granule cells from surgically resected hippocampal specimens from patients with mesial temporal lobe epilepsy with and without hippocampal sclerosis, we have demonstrated the utility of next-generation sequencing methods for producing biologically relevant results from small populations of homogeneous cells, and have provided insight on the transcriptional changes associated with this pathology.

Project description:Temporal lobe epilepsy is associated with large-scale, wide-ranging changes in gene expression in the hippocampus. Epigenetic changes to DNA are attractive mechanisms to explain the sustained hyperexcitability of chronic epilepsy. Here, through methylation analysis of all annotated C-phosphate-G islands and promoter regions in the human genome, we report a pilot study of the methylation profiles of temporal lobe epilepsy with or without hippocampal sclerosis. Furthermore, by comparative analysis of expression and promoter methylation, we identify methylation sensitive non-coding RNA in human temporal lobe epilepsy. A total of 146 protein-coding genes exhibited altered DNA methylation in temporal lobe epilepsy hippocampus (n = 9) when compared to control (n = 5), with 81.5% of the promoters of these genes displaying hypermethylation. Unique methylation profiles were evident in temporal lobe epilepsy with or without hippocampal sclerosis, in addition to a common methylation profile regardless of pathology grade. Gene ontology terms associated with development, neuron remodelling and neuron maturation were over-represented in the methylation profile of Watson Grade 1 samples (mild hippocampal sclerosis). In addition to genes associated with neuronal, neurotransmitter/synaptic transmission and cell death functions, differential hypermethylation of genes associated with transcriptional regulation was evident in temporal lobe epilepsy, but overall few genes previously associated with epilepsy were among the differentially methylated. Finally, a panel of 13, methylation-sensitive microRNA were identified in temporal lobe epilepsy including MIR27A, miR-193a-5p (MIR193A) and miR-876-3p (MIR876), and the differential methylation of long non-coding RNA documented for the first time. The present study therefore reports select, genome-wide DNA methylation changes in human temporal lobe epilepsy that may contribute to the molecular architecture of the epileptic brain.

Project description:Mesial temporal lobe epilepsy (MTLE), one of the most common types of refractory focal epilepsy, has shown white matter abnormalities both within and beyond the temporal lobe. In particular, the white matter abnormalities in the ipsilateral hemisphere are more obvious than those in the contralateral hemisphere in MTLE, that is, the abnormalities present asymmetrical characteristics. However, very few studies have characterized the white matter microstructure asymmetry in MTLE patients specifically. Thus, we performed diffusion tensor imaging (DTI) to investigate the white matter microstructure asymmetries of patients with MTLE with unilateral hippocampal sclerosis (MTLE-HS). We enrolled 25 MTLE-HS (left MTLE-HS group, n = 13; right MTLE-HS group, n = 12) and 26 healthy controls (HC). DTI data were analyzed by tract-based spatial statistics (TBSS) to test the hemispheric differences across the entire white matter skeleton. We also conducted a two-sample paired t-test for 21 paired region of interests (ROIs) parceled on the basis of the ICBM-DTI-81 white-matter label atlas of bilateral hemispheres to test the hemispheric differences. An asymmetry index (AI) was calculated to further quantify the differences between the left and right paired-ROIs. It was found that the asymmetries of white matter skeletons were significantly lower in the MTLE-HS groups than in the HC group. In particular, the asymmetry traits were moderately reduced in the RMTLE-HS group and obviously reduced in the LMTLE-HS group. In addition, AI was significantly different in the RMTLE-HS group from the LMTLE-HS or HC group in the limbic system and superior longitudinal fasciculus (SLF). The current study found that the interhemispheric white matter asymmetries were significantly reduced in the MTLE-HS groups than in the HC group. The interhemispheric white matter asymmetries are distinctly affected in left and right MTLE-HS groups. The differences in AI among RMTLE-HS, LMTLE-HS, and HC involved the limbic system and SLF, which may have some pragmatic implications for the diagnosis of MTLE and differentiating LMTLE-HS from RMTLE-HS.

Project description:ObjectivePatients with temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) have diffuse subtle gray matter (GM) atrophy detectable by MRI quantification analyses. However, it is not clear whether the etiology and seizure frequency are associated with this atrophy. We aimed to evaluate the occurrence of GM atrophy and the influence of seizure frequency in patients with TLE and either normal MRI (TLE-NL) or MRI signs of HS (TLE-HS).MethodsWe evaluated a group of 172 consecutive patients with unilateral TLE-HS or TLE-NL as defined by hippocampal volumetry and signal quantification (122 TLE-HS and 50 TLE-NL) plus a group of 82 healthy individuals. Voxel-based morphometry was performed with VBM8/SPM8 in 3T MRIs. Patients with up to three complex partial seizures and no generalized tonic-clonic seizures in the previous year were considered to have infrequent seizures. Those who did not fulfill these criteria were considered to have frequent seizures.ResultsPatients with TLE-HS had more pronounced GM atrophy, including the ipsilateral mesial temporal structures, temporal lobe, bilateral thalami and pre/post-central gyri. Patients with TLE-NL had more subtle GM atrophy, including the ipsilateral orbitofrontal cortex, bilateral thalami and pre/post-central gyri. Both TLE-HS and TLE-NL showed increased GM volume in the contralateral pons. TLE-HS patients with frequent seizures had more pronounced GM atrophy in extra-temporal regions than TLE-HS with infrequent seizures. Patients with TLE-NL and infrequent seizures had no detectable GM atrophy. In both TLE-HS and TLE-NL, the duration of epilepsy correlated with GM atrophy in extra-hippocampal regions.ConclusionAlthough a diffuse network GM atrophy occurs in both TLE-HS and TLE-NL, this is strikingly more evident in TLE-HS and in patients with frequent seizures. These findings suggest that neocortical atrophy in TLE is related to the ongoing seizures and epilepsy duration, while thalamic atrophy is more probably related to the original epileptogenic process.

Dataset Information

Differential expression of miR-184 in temporal lobe epilepsy patients with and without hippocampal sclerosis - Influence on microglial function.

Publications

Differential expression of miR-184 in temporal lobe epilepsy patients with and without hippocampal sclerosis - Influence on microglial function.

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