Dataset Information

Reduced mature microRNA levels in association with dicer loss in human temporal lobe epilepsy with hippocampal sclerosis.

ABSTRACT: Hippocampal sclerosis (HS) is a common pathological finding in patients with temporal lobe epilepsy (TLE) and is associated with altered expression of genes controlling neuronal excitability, glial function, neuroinflammation and cell death. MicroRNAs (miRNAs), a class of small non-coding RNAs, function as post-transcriptional regulators of gene expression and are critical for normal brain development and function. Production of mature miRNAs requires Dicer, an RNAase III, loss of which has been shown to cause neuronal and glial dysfunction, seizures, and neurodegeneration. Here we investigated miRNA biogenesis in hippocampal and neocortical resection specimens from pharmacoresistant TLE patients and autopsy controls. Western blot analysis revealed protein levels of Dicer were significantly lower in certain TLE patients with HS. Dicer levels were also reduced in the hippocampus of mice subject to experimentally-induced epilepsy. To determine if Dicer loss was associated with altered miRNA processing, we profiled levels of 380 mature miRNAs in control and TLE-HS samples. Expression of nearly 200 miRNAs was detected in control human hippocampus. In TLE-HS samples there was a large-scale reduction of miRNA expression, with 51% expressed at lower levels and a further 24% not detectable. Primary transcript (pri-miRNAs) expression levels for several tested miRNAs were not different between control and TLE-HS samples. These findings suggest loss of Dicer and failure of mature miRNA expression may be a feature of the pathophysiology of HS in patients with TLE.

SUBMITTER: McKiernan RC

PROVIDER: S-EPMC3352899 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Reduced mature microRNA levels in association with dicer loss in human temporal lobe epilepsy with hippocampal sclerosis.

McKiernan Ross C RC Jimenez-Mateos Eva M EM Bray Isabella I Engel Tobias T Brennan Gary P GP Sano Takanori T Michalak Zuzanna Z Moran Catherine C Delanty Norman N Farrell Michael M O'Brien Donncha D Meller Robert R Simon Roger P RP Stallings Raymond L RL Henshall David C DC

PloS one 20120515 5

Hippocampal sclerosis (HS) is a common pathological finding in patients with temporal lobe epilepsy (TLE) and is associated with altered expression of genes controlling neuronal excitability, glial function, neuroinflammation and cell death. MicroRNAs (miRNAs), a class of small non-coding RNAs, function as post-transcriptional regulators of gene expression and are critical for normal brain development and function. Production of mature miRNAs requires Dicer, an RNAase III, loss of which has been ...[more]

PMID: 22615744

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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:BackgroundIncreasing evidence supports the role of soluble inflammatory mediators in the pathogenesis of refractory temporal lobe epilepsy (TLE). Hippocampal sclerosis (HS) is a well-described pathohistological abnormality in TLE. The association of proinflammatory cytokines with epileptic disease profiles is well established; however, the potential significance of circulating interleukin 10 (IL-10), particularly in TLE-associated HS, is still poorly understood. Therefore, taking into consideration the neuroprotective and anticonvulsive effects of IL-10, we performed this study to examine the role of the plasma levels of IL-10 in patients with TLE with HS (TLE?+?HS), TLE without HS (TLE-HS) and with other types of epilepsy.MethodsThis study included 270 patients with refractory epilepsy who were classified into four groups: i) 34 patients with TLE?+?HS, ii) 105 patients with TLE-HS, iii) 95 patients with extra-TLE (XLE) and iv) 36 patients with idiopathic generalized epilepsy (IGE). The plasma IL-10 levels were quantified using a commercially available enzyme-linked immunosorbent assay (ELISA).ResultsIL-10 levels were significantly lower in TLE?+?HS than in TLE-HS (p?=?0.013). In a subgroup of TLE-HS patients who had seizures 1 month before sampling, patients with seizures had significantly higher IL-10 levels than patients who were seizure-free (p?=?0.039). Among a small group (n?=?15) of non-refractory TLE-HS patients, IL-10 levels showed a moderate negative correlation with the duration of epilepsy (r?=?-?0.585, p?=?0.023).ConclusionsThis study demonstrated that chronically reduced levels of plasma IL-10 were associated with HS in TLE patients, suggesting that there was an inadequate systemic anti-inflammatory immune response. These results could provide new biological insights into the pathophysiology of HS in TLE. We also found that the production of IL-10 could be affected by the seizure frequency and declined concomitantly with increased disease durations. Therefore, the measurement of plasma IL-10 may have diagnostic value as a biomarker for stratifying TLE?+?HS from other epilepsy types or as a marker of disease progression towards a progressive form of epilepsy.

Dataset Information

Reduced mature microRNA levels in association with dicer loss in human temporal lobe epilepsy with hippocampal sclerosis.

Publications

Reduced mature microRNA levels in association with dicer loss in human temporal lobe epilepsy with hippocampal sclerosis.

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