Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Meibergdreef 9, Amsterdam, the Netherlands.
Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Meibergdreef 9, Amsterdam, the Netherlands; Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, the Netherlands.
Neurobiol Dis. 2020 Feb;134:104612. doi: 10.1016/j.nbd.2019.104612. Epub 2019 Sep 15.
Our understanding of mesial temporal lobe epilepsy (MTLE), one of the most common form of drug-resistant epilepsy in humans, is derived mainly from clinical, imaging, and physiological data from humans and animal models. High-throughput gene expression studies of human MTLE have the potential to uncover molecular changes underlying disease pathogenesis along with novel therapeutic targets. Using RNA- and small RNA-sequencing in parrallel, we explored differentially expressed genes in the hippocampus and cortex of MTLE patients who had undergone surgical resection and non-epileptic controls. We identified differentially expressed genes in the hippocampus of MTLE patients and differentially expressed small RNAs across both the cortex and hippocampus. We found significant enrichment for astrocytic and microglial genes among up-regulated genes, and down regulation of neuron specific genes in the hippocampus of MTLE patients. The transcriptome profile of the small RNAs reflected disease state more robustly than mRNAs, even across brain regions which show very little pathology. While mRNAs segregated predominately by brain region for MTLE and controls, small RNAs segregated by disease state. In particular, our data suggest that specific miRNAs (e.g., let-7b-3p and let-7c-3p) may be key regulators of multiple pathways related to MTLE pathology. Further, we report a strong association of other small RNA species with MTLE pathology. As such we have uncovered novel elements that may contribute to the establishment and progression of MTLE pathogenesis and that could be leveraged as therapeutic targets.
我们对内侧颞叶癫痫（MTLE）的理解主要来自于人类和动物模型的临床、影像和生理数据。高通量基因表达研究人类 MTLE 有可能揭示疾病发病机制的分子变化以及新的治疗靶点。我们使用 RNA 和小 RNA 测序平行探索了接受手术切除的 MTLE 患者和非癫痫对照的海马和皮层中差异表达的基因。我们在 MTLE 患者的海马体中发现了差异表达的基因，在皮层和海马体中发现了差异表达的小 RNA。在 MTLE 患者的海马体中，上调基因中存在明显的星形胶质细胞和小胶质细胞基因富集，神经元特异性基因下调。小 RNA 的转录组谱比 mRNAs 更能反映疾病状态，即使在病理变化很小的脑区也是如此。虽然 mRNAs 主要按脑区对 MTLE 和对照进行分类，但小 RNA 则按疾病状态进行分类。特别是，我们的数据表明，特定的 miRNAs（例如 let-7b-3p 和 let-7c-3p）可能是与 MTLE 病理相关的多个途径的关键调节剂。此外，我们报告了其他小 RNA 物种与 MTLE 病理之间的强烈关联。因此，我们已经发现了可能有助于 MTLE 发病机制建立和进展的新元素，并且可以将其作为治疗靶点。
