Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Pittsburgh Institute for Neurodegenerative Diseases (PIND), University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Pittsburgh Institute for Neurodegenerative Diseases (PIND), University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Mol Genet Metab. 2019 Apr;126(4):439-447. doi: 10.1016/j.ymgme.2019.01.008. Epub 2019 Jan 17.
Seizures are a feature not only of the many forms of epilepsy, but also of global metabolic diseases such as mitochondrial encephalomyopathy (ME) and glycolytic enzymopathy (GE). Modern anti-epileptic drugs (AEDs) are successful in many cases, but some patients are refractory to existing AEDs, which has led to a surge in interest in clinically managed dietary therapy such as the ketogenic diet (KD). This high-fat, low-carbohydrate diet causes a cellular switch from glycolysis to fatty acid oxidation and ketone body generation, with a wide array of downstream effects at the genetic, protein, and metabolite level that may mediate seizure protection. We have recently shown that a Drosophila model of human ME (ATP6) responds robustly to the KD; here, we have investigated the mechanistic importance of the major metabolic consequences of the KD in the context of this bioenergetics disease: ketogenesis, reduction of glycolysis, and anaplerosis. We have found that reduction of glycolysis does not confer seizure protection, but that dietary supplementation with ketone bodies or the anaplerotic lipid triheptanoin, which directly replenishes the citric acid cycle, can mimic the success of the ketogenic diet even in the presence of standard carbohydrate levels. We have also shown that the proper functioning of the citric acid cycle is crucial to the success of the KD in the context of ME. Furthermore, our data reveal that multiple seizure models, in addition to ATP6, are treatable with the ketogenic diet. Importantly, one of these mutants is TPI, which models human glycolytic enzymopathy, an incurable metabolic disorder with severe neurological consequences. Overall, these studies reveal widespread success of the KD in Drosophila, further cementing its status as an excellent model for studies of KD treatment and mechanism, and reveal key insights into the therapeutic potential of dietary therapy against neuronal hyperexcitability in epilepsy and metabolic disease.
癫痫发作不仅是多种形式癫痫的特征，也是全球性代谢疾病的特征，如线粒体脑肌病（ME）和糖酵解酶病（GE）。现代抗癫痫药物（AEDs）在许多情况下都很成功，但有些患者对现有的 AEDs 有抗药性，这导致人们对临床管理的饮食疗法（如生酮饮食（KD））产生了浓厚的兴趣。这种高脂肪、低碳水化合物的饮食会导致细胞从糖酵解切换到脂肪酸氧化和酮体生成，从而在遗传、蛋白质和代谢物水平上产生广泛的下游效应，这些效应可能介导癫痫保护。我们最近表明，人类 ME（ATP6）的果蝇模型对 KD 反应强烈；在这里，我们研究了 KD 在这种生物能量疾病背景下对主要代谢后果的机制重要性：酮体生成、糖酵解减少和氨酰化。我们发现，糖酵解减少并不能提供癫痫保护，但饮食补充酮体或氨酰化脂质三庚酸酯（直接补充柠檬酸循环），即使在标准碳水化合物水平存在的情况下，也可以模拟生酮饮食的成功。我们还表明，柠檬酸循环的正常功能对于 ME 背景下 KD 的成功至关重要。此外，我们的数据表明，除了 ATP6 之外，还有多种癫痫模型可以用生酮饮食治疗。重要的是，其中一个突变体是 TPI，它模拟了人类糖酵解酶病，这是一种无法治愈的代谢紊乱，会导致严重的神经后果。总的来说，这些研究在果蝇中广泛证明了 KD 的成功，进一步巩固了它作为 KD 治疗和机制研究的优秀模型的地位，并揭示了饮食治疗对癫痫和代谢性疾病中神经元过度兴奋的治疗潜力的关键见解。
