Mechanisms of epilepsy-related death in Leigh syndrome

NDUFS4基因功能丧失突变，该基因编码蛋白复合体I的一个亚单位 线粒体电子传递链与Leigh综合征(LS)密切相关。LS，或亚急性 坏死性脑病，是一种衰弱的进行性神经退行性疾病。它通常会呈现出 导致残疾并最终在3岁前死亡的多系统临床症状。 由Ndufs4的全局或CNS特异性敲除(KO)产生的LS的小鼠模型显示了几个关键 人类LS的临床特征，包括发育迟缓，生长迟缓，共济失调，低眼压，视力问题， 呼吸不规律，自发性癫痫发作和死亡。我们对条件NDUFS4的初步研究 KO小鼠发现癫痫表型可以从LS的大多数其他特征中分离出来，使用 遗传方法。GABA能(非谷氨酸能)神经元Ndufs4选择性KO引起自发性 癫痫发作并导致小鼠猝死。因此，这项提案中的工作将探索耐人寻味的 Ndufs4可能是SUDEP基因，由其KO引起的GABA能神经元功能障碍是主要的 LS小鼠癫痫和SUDEP的病因。事实上，这些小鼠提供了一个独特的机会， 与LS引起的Ndufs4突变相关的SUDEP风险特别是与神经元间功能障碍相关的研究 总体而言。 有趣的是，目前的基因发现研究假设SUDEP基因可能最好被识别为一种 通过中枢或外周引起癫痫并增加SUDEP风险的突变或致病变异 神经系统或终末器官对呼吸、心脏或其他自主功能的影响。前脑 包括已知参与癫痫发作产生的区域，脑干包括控制中心 对于自主神经功能，通常在SUDEP中受到影响。在这个项目中，我们将研究中间神经元的作用。 利氏综合征癫痫小鼠模型中SUDEP机制的功能障碍。我们将：(1)比较 兴奋性神经元和抑制性神经元Ndufs4-KO对SUDEP的作用 (2)比较Ndufs4KO在前脑(Dlxcre12)和脑干中的贡献 (通过病毒cre)LS小鼠GABA能神经元对SUDEP的敏感性；以及(3)确定固有的变化。 前脑中间神经元的突触功能与癫痫和超感诱发电位的病理生理关系 老鼠。这些研究的发现将为深入了解利的猝死机制提供帮助。 综合征，是儿童最常见的线粒体疾病形式。

Loss-of-function mutations in NDUFS4, the gene that encodes a subunit of the protein complex I in the mitochondrial electron transport chain, are strongly associated with Leigh Syndrome (LS). LS, or subacute necrotizing encephalopathy, is a debilitating progressive neurodegenerative disorder. It typically presents with multi-systemic clinical symptoms which result in disability and ultimately death by 3 years of age. Mouse models of LS, generated by global or CNS specific Knock Out (KO) of Ndufs4, exhibit several key clinical features of human LS, including failure to thrive, growth retardation, ataxia, hypotonia, visual problems, breathing irregularities, and spontaneous seizures and deaths. Our preliminary studies of conditional Ndufs4 KO mice reveal that the epilepsy phenotype can be dissociated from most of the other features of LS, using genetic approaches. Selective KO of Ndufs4 in GABAergic (not glutamatergic) neurons causes spontaneous seizures and leads to sudden death in mice. Therefore, work in this proposal will explore the intriguing possibility that Ndufs4 is a SUDEP gene and GABAergic neuron dysfunction, caused by its KO, is the principal cause of epilepsy and SUDEP in LS mice. Indeed, these mice present a unique opportunity for functional studies of SUDEP risks associated with LS-causing Ndufs4 mutation in particular and interneuron dysfunction in general. Interestingly, current gene discovery studies have postulated that a SUDEP gene might be best identified as a mutation or pathogenic variant that causes epilepsy and increases SUDEP risk via central or peripheral nervous system or end-organ effects on respiratory, cardiac, or other autonomic functions. The forebrain includes regions known to be involved in seizure generation and the brainstem encompasses control centers for autonomic functions, commonly affected in SUDEP. In this project, we will examine the role of interneuron dysfunction in mechanisms SUDEP in Leigh syndrome epilepsy using mouse models. We will: (1) Compare the contributions of Ndufs4 KO in excitatory (by Vglut2cre) and inhibitory (by Gad2cre) neurons to SUDEP susceptibility in LS mice; (2) compare the contributions of Ndufs4 KO in forebrain (by Dlxcre12) and brainstem (by viral cre) GABAergic neurons to SUDEP susceptibility in LS mice; and (3) determine changes in intrinsic and synaptic functions of forebrain interneurons that contribute to epilepsy and SUDEP pathophysiology in LS mice. Findings from these studies will provide insights into the mechanisms of sudden death in Leigh syndrome, the most common form of mitochondrial disorder in children.