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.

Public Health Relevance

Studies in this project will investigate the role of GABAergic interneurons in the mechanisms of seizure-induced cardiorespiratory dysfunctions and ensuing Sudden Unexpected Death in a mouse model of Leigh Syndrome Epilepsy. Leigh syndrome is a devastating infantile progressive neurodegenerative disorder due to mitochondrial dysfunction.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Whittemore, Vicky R
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Seattle Children's Hospital
United States
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