Home > Articles > Published articles > Defined neuronal populations drive fatal phenotype in a mouse model of leigh syndrome |
Date: | 2019 |
Abstract: | Mitochondrial deficits in energy production cause untreatable and fatal pathologies known as mitochondrial disease (MD). 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 Vglut2expressing 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. |
Grants: | Ministerio de Economía y Competitividad JCI-2015-24576 Ministerio de Economía y Competitividad BES-2015-073041 Ministerio de Economía y Competitividad RyC-2012-1187 Ministerio de Economía y Competitividad SAF2014-57981P Ministerio de Economía y Competitividad SAF2017-88108-R European Commission 665919 European Commission 658352 Ministerio de Ciencia e Innovación RTI2018-101838-J-I00 Instituto de Salud Carlos III CB06-05-1105 Instituto de Salud Carlos III RD16-0011-0014 European Commission 638106 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-323 |
Note: | Altres ajuts: Seattle Children's Research Institute: Seed Funds;NINDS: R01 NIH/NS 102796; University of Washington Neurological Surgery Department: Ellenbogen Neurological Surgery Research Funds; University of Washington: The Ryan J. Murphy SUDEP Research Funds; Mitochondrial Research Guild: Seed Funds |
Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. |
Language: | Anglès |
Document: | Article ; recerca ; Versió publicada |
Published in: | eLife, Vol. 8 (august 2019) , p. e47163, ISSN 2050-084X |
26 p, 4.7 MB |