Pires Geoffrey, Leitner Dominique, Drummond Eleanor, Kanshin Evgeny, Nayak Shruti, Askenazi Manor, Faustin Arline, Friedman Daniel, Debure Ludovic, Ueberheide Beatrix, Wisniewski Thomas, Devinsky Orrin
Comprehensive Epilepsy Center, New York University Grossman School of Medicine, New York, NY, USA.
Department of Neurology, Center for Cognitive Neurology, New York University Grossman School of Medicine, New York, NY, USA.
Brain Commun. 2021 Mar 9;3(2):fcab021. doi: 10.1093/braincomms/fcab021. eCollection 2021.
Epilepsy is a common neurological disorder affecting over 70 million people worldwide, with a high rate of pharmaco-resistance, diverse comorbidities including progressive cognitive and behavioural disorders, and increased mortality from direct (e.g. sudden unexpected death in epilepsy, accidents, drowning) or indirect effects of seizures and therapies. Extensive research with animal models and human studies provides limited insights into the mechanisms underlying seizures and epileptogenesis, and these have not translated into significant reductions in pharmaco-resistance, morbidities or mortality. To help define changes in molecular signalling networks associated with seizures in epilepsy with a broad range of aetiologies, we examined the proteome of brain samples from epilepsy and control cases. Label-free quantitative mass spectrometry was performed on the hippocampal cornu ammonis 1-3 region (CA1-3), frontal cortex and dentate gyrus microdissected from epilepsy and control cases ( = 14/group). Epilepsy cases had significant differences in the expression of 777 proteins in the hippocampal CA1 - 3 region, 296 proteins in the frontal cortex and 49 proteins in the dentate gyrus in comparison to control cases. Network analysis showed that proteins involved in protein synthesis, mitochondrial function, G-protein signalling and synaptic plasticity were particularly altered in epilepsy. While protein differences were most pronounced in the hippocampus, similar changes were observed in other brain regions indicating broad proteomic abnormalities in epilepsy. Among the most significantly altered proteins, G-protein subunit beta 1 (GNB1) was one of the most significantly decreased proteins in epilepsy in all regions studied, highlighting the importance of G-protein subunit signalling and G-protein-coupled receptors in epilepsy. Our results provide insights into common molecular mechanisms underlying epilepsy across various aetiologies, which may allow for novel targeted therapeutic strategies.
癫痫是一种常见的神经系统疾病，全球有超过7000万人受其影响，具有较高的药物耐受性，伴有多种合并症，包括进行性认知和行为障碍，且因癫痫发作及治疗的直接（如癫痫猝死、事故、溺水）或间接影响导致死亡率增加。对动物模型和人体研究的广泛探索，对癫痫发作和癫痫发生的潜在机制提供的见解有限，这些研究尚未转化为药物耐受性、发病率或死亡率的显著降低。为了帮助确定与多种病因引起的癫痫发作相关的分子信号网络变化，我们检查了癫痫患者和对照病例的脑样本蛋白质组。对从癫痫患者和对照病例（每组14例）中显微切割得到的海马角回1-3区（CA1-3）、额叶皮质和齿状回进行无标记定量质谱分析。与对照病例相比，癫痫患者海马CA1-3区有777种蛋白质表达存在显著差异，额叶皮质有296种蛋白质表达存在显著差异，齿状回有49种蛋白质表达存在显著差异。网络分析表明，参与蛋白质合成、线粒体功能、G蛋白信号传导和突触可塑性的蛋白质在癫痫中尤其发生了改变。虽然蛋白质差异在海马中最为明显，但在其他脑区也观察到了类似变化，表明癫痫存在广泛的蛋白质组异常。在变化最显著的蛋白质中，G蛋白亚基β1（GNB1）是所有研究区域中癫痫患者体内表达显著降低的蛋白质之一，突出了G蛋白亚基信号传导和G蛋白偶联受体在癫痫中的重要性。我们的研究结果为各种病因引起的癫痫的共同分子机制提供了见解，这可能有助于制定新的靶向治疗策略。
