Increased Reelin Promoter Methylation Is Associated With Granule Cell Dispersion in Human Temporal Lobe Epilepsy
Increased Reelin Promoter Methylation Is Associated With Granule Cell Dispersion in Human Temporal Lobe Epilepsy
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DOI：
10.1097/nen.0b013e31819ba737
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发表时间：
2009-04-01
影响因子：
3.2
通讯作者：
Bluemcke, Ingmar
中科院分区：
文献类型：
--
作者：
Kobow, Katja;Jeske, Ina;Bluemcke, Ingmar
中颞叶硬化（MTS）是慢性难治性颞叶癫痫（TLE）中最常见的病变，其特征是海马主要节段的神经元细胞损失。另一个组织病理学特征包括颗粒细胞弥散（GCD），大约50%的中颞叶硬化症患者会遇到齿状回的结构紊乱。Reelin是由齿状分子层Cajal-Retzius细胞合成和释放的，在海马的发育和层流组织的维持中起着关键作用，先前的研究表明Reelin在人类颞叶癫痫标本中转录水平下调。为了研究Reelin启动子甲基化导致的表观遗传沉默是否可能是GCD的所有潜在致病机制，从9例GCD MTS标本、5例未GCD TLE标本和3例尸检对照中采集了3个微解剖海马亚区（即齿状回和下背前的分子和颗粒细胞层）的DNA，在亚硫酸盐处理、克隆和直接测序后分析了启动子甲基化；免疫组化法鉴定Cajal-Retzius细胞。发现在TLE标本中，Reelin启动子甲基化程度高于对照组；在TLE标本中，启动子甲基化与GCD相关（p < 0.0002）。没有其他临床或组织病理学参数（即性别、年龄、癫痫发作持续时间、MTS的药物或程度）与启动子甲基化相关。这些数据支持受损的Reel in信号通路，并确定启动子甲基化是TLE发病机制中的表观遗传机制。
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 all underlying pathogenetic mechanism of GCD, DNA was harvested front 3 microdissected hippocampal subregions (i.e. molecular and granule Cell layers of the dentate gyrus and presubiculum) from 9 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 ill 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 Reel in-signaling pathway and identify promoter methylation as an epigenetic mechanism in the pathogenesis of TLE.