Enhancing glucose metabolism via gluconeogenesis is therapeutic in a zebrafish model of Dravet syndrome.
Enhancing glucose metabolism via gluconeogenesis is therapeutic in a zebrafish model of Dravet syndrome.
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DOI：
10.1093/braincomms/fcab004
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发表时间：
2021
影响因子：
4.8
通讯作者：
Patel M
中科院分区：
文献类型：
--
作者：
Banerji R;Huynh C;Figueroa F;Dinday MT;Baraban SC;Patel M
能量产生途径是治疗神经发育障碍的新靶点。在这里，我们专注于纠正由钠通道Nav1.1基因SCN1a突变引起的灾难性的儿科癫痫-Dravet综合征的代谢缺陷。我们利用了一个可翻译的Drave氏综合征斑马鱼模型(Scn1Lab)，该模型显示了Drave氏综合征患者的关键特征，并显示了代谢缺陷，并伴随着糖异生基因pck 1和pck 2的下调。利用基于新陈代谢的小文库筛选，我们鉴定了通过上调scn1Lab幼虫中pck 1基因表达来促进糖异生的化合物。用PK11195处理突变幼虫，可使异常调节的血糖水平、代谢缺陷、转位蛋白表达正常化，并显著减少脑电惊厥。在野生型幼虫中抑制PCK1与在scn1lab突变体中观察到的代谢和行为缺陷相似。综上所述，这表明纠正Dys调节的代谢途径可以治疗神经发育障碍，如离子通道功能障碍引起的Drave综合征。Banerji等人。他发现了一种糖异生调节剂PK11195，这是一种已知的线粒体转位蛋白配体，可以在临床前的德拉韦综合征斑马鱼模型中使代谢缺陷正常化并抑制脑电发作。这表明了一种新的基于新陈代谢的治疗方法来治疗灾难性的儿科癫痫，如由离子通道突变引起的德拉韦综合征。
Energy-producing pathways are novel therapeutic targets for the treatment of neurodevelopmental disorders. Here, we focussed on correcting metabolic defects in a catastrophic paediatric epilepsy, Dravet syndrome which is caused by mutations in sodium channel NaV1.1 gene, SCN1A. We utilized a translatable zebrafish model of Dravet syndrome (scn1lab) which exhibits key characteristics of patients with Dravet syndrome and shows metabolic deficits accompanied by down-regulation of gluconeogenesis genes, pck1 and pck2. Using a metabolism-based small library screen, we identified compounds that increased gluconeogenesis via up-regulation of pck1 gene expression in scn1lab larvae. Treatment with PK11195, a pck1 activator and a translocator protein ligand, normalized dys-regulated glucose levels, metabolic deficits, translocator protein expression and significantly decreased electrographic seizures in mutant larvae. Inhibition of pck1 in wild-type larvae mimicked metabolic and behaviour defects observed in scn1lab mutants. Together, this suggests that correcting dys-regulated metabolic pathways can be therapeutic in neurodevelopmental disorders such as Dravet syndrome arising from ion channel dysfunction. Banerji et al. identified a gluconeogenesis modulator, PK11195, a known mitochondrial translocator protein ligand that normalized metabolic deficits and suppressed electrographic seizures in a pre-clinical zebrafish model of Dravet syndrome. This suggests a novel metabolism-based therapeutic avenue to treat catastrophic paediatric epilepsies such as Dravet syndrome arising from ion channel mutations.
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