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Central nervous system affectation is critical in Leigh Syndrome (LS), a common MD presentation, leading to motor and respiratory deficits, seizures and premature death. However, only specific neuronal populations are affected. Furthermore, their molecular identity and their contribution to the disease remains unknown. Here, using a mouse model of LS lacking the mitochondrial complex I subunit Ndufs4, we dissect the critical role of genetically-defined neuronal populations in LS progression. Ndufs4 inactivation in Vglut2-expressing glutamatergic neurons leads to decreased neuronal firing, brainstem inflammation, motor and respiratory deficits, and early death. In contrast, Ndufs4 deletion in GABAergic neurons causes basal ganglia inflammation without motor or respiratory involvement, but accompanied by hypothermia and severe epileptic seizures preceding death. These results provide novel insight in the cell type-specific contribution to the pathology, dissecting the underlying cellular mechanisms of MD.<\/jats:p>","DOI":"10.7554\/elife.47163","type":"journal-article","created":{"date-parts":[[2019,8,12]],"date-time":"2019-08-12T08:00:19Z","timestamp":1565596819000},"source":"Crossref","is-referenced-by-count":66,"title":["Defined neuronal populations drive fatal phenotype in a mouse model of Leigh syndrome"],"prefix":"10.7554","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9591-980X","authenticated-orcid":true,"given":"Irene","family":"Bolea","sequence":"first","affiliation":[{"name":"Center for Developmental Therapeutics, Seattle Children\u2019s Research Institute, Seattle, United States"},{"name":"Institut de Neuroci\u00e8ncies, Universitat Aut\u00f2noma de Barcelona, Bellaterra, 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