Defined neuronal populations drive fatal phenotype in a mouse model of Leigh Syndrome
- Seattle Children's Research Institute, United States
- Universitat Autònoma de Barcelona, Spain
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 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.
Data availability
Normalized and raw data have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (accession number GSE125470).
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Gene expression analysis in the Brainstem of Vglut2:Ndufs4cKO miceNCBI Gene Expression Omnibus, GSE125470.
Article and author information
Author details
Pablo Machuca-Márquez
Funding
Ministerio de Economía y Competitividad (JCI-2015-24576)
- Irene Bolea
Ministerio de Economía y Competitividad (SAF2017-88108-R)
- Albert Quintana
Agència de Gestió d'Ajuts Universitaris i de Recerca (2017SGR- 323)
- Albert Quintana
CIBERNED (CB06/05/1105)
- Xavier Navarro
TERCEL (RD16/0011/0014)
- Xavier Navarro
Instituto de Salud Carlos III
- Xavier Navarro
European Regional Development Funds
- Xavier Navarro
Ministerio de ciencia, investigación y universidades (RTI2018-101838-J-I00)
- Elisenda Sanz
European Commission (H2020-MSCA-COFUND-2014-665919)
- Alejandro Gella
European Commission (H2020-MSCA-IF-2014-658352)
- Elisenda Sanz
Ministerio de Economía y Competitividad (BES-2015-073041)
- Patricia Prada-Dacasa
Seattle Children's Research Institute (Seed Funds)
- Albert Quintana
Northwest Mitochondrial Guild (Seed Funds)
- Albert Quintana
Ministerio de Economía y Competitividad (RyC-2012-1187)
- Albert Quintana
European Research Council (ERC-2014-StG-638106)
- Albert Quintana
Ministerio de Economía y Competitividad (SAF2014-57981P)
- Albert Quintana
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were conducted following the recommendations in the Guide for the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee of the Seattle Children´s Research Institute (#00108) and Universitat Autònoma de Barcelona (CEEAH 2925, 3295, 4114, 4155). All surgeries were performed under anesthesia, and every effor was made to minimize suffering.
Copyright
© 2019, Bolea et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Defined neuronal populations drive fatal phenotype in a mouse model of Leigh Syndrome
eLife 8:e47163.
https://doi.org/10.7554/eLife.47163
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