A conserved epilepsy-associated gene co-expression module identifies increased metabolic rate as a shared pathomechanism.

IF 3.3 3区 医学 Q2 CELL BIOLOGY
Jingyi Long, Spencer G Jones, Ana Serna, Boyd van Reijmersdal, Franziska Kampshoff, Sara Aibar, Patrik Verstreken, Martijn A Huynen, Kevin Lüthy, Mireia Coll-Tané, Annette Schenck
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引用次数: 0

Abstract

Epilepsy is a mechanistically complex, incompletely understood neurological disorder. To uncover novel converging mechanisms in epilepsy, we used Drosophila whole-brain single-cell RNA sequencing to refine and characterize a previously proposed human epilepsy-associated gene co-expression network (GCN). We identified a conserved co-expressed module of 26 genes, which comprises fly orthologs of 13 epilepsy-associated genes and integrates synaptic and metabolic functions. Over one-third of the Drosophila pan-neuronal knockdown models targeting this module exhibited altered seizure-like behaviors in response to mechanical or heat stress. These knockdown models recapitulated seizures associated with four epilepsy-associated genes, identified two novel epilepsy candidate genes, and three genes of which knockdown conferred seizure protection. Most knockdown models with altered seizure susceptibility showed changes in metabolic rate and levels of phosphorylated adenosine monophosphate-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis. Enhancing AMPK activity increased seizure resistance in a dose-dependent manner. Our findings show that Drosophila single-cell expression data and behavior can aid functional validation of human GCNs and highlight a role for metabolism in modifying seizure susceptibility.

保守的癫痫相关基因共表达模块确定代谢率增加是一个共同的病理机制。
癫痫是一种机制复杂、尚未完全了解的神经系统疾病。为了揭示癫痫的新趋同机制,我们使用果蝇全脑单细胞RNA测序来完善和表征先前提出的人类癫痫相关基因共表达网络(GCN)。我们发现了一个保守的共表达模块,包含26个基因,其中包括13个癫痫相关基因的苍蝇同源基因,并整合了突触和代谢功能。针对该模块的果蝇泛神经元敲除模型中,超过三分之一的模型在机械或热应激下表现出癫痫样行为的改变。这些敲低模型重现了与四种癫痫相关基因相关的癫痫发作,确定了两个新的癫痫候选基因,以及三个敲低具有癫痫发作保护作用的基因。大多数具有癫痫易感性改变的敲低模型显示代谢率和磷酸化腺苷单磷酸活化蛋白激酶(AMPK)水平的变化,AMPK是细胞能量稳态的关键调节因子。增强AMPK活性以剂量依赖的方式增加癫痫抵抗。我们的研究结果表明,果蝇单细胞表达数据和行为可以帮助人类GCNs的功能验证,并强调代谢在改变癫痫易感性中的作用。
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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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