2. Academic Validation
  3. Defined neuronal populations drive fatal phenotype in a mouse model of Leigh syndrome

Defined neuronal populations drive fatal phenotype in a mouse model of Leigh syndrome

  • Elife. 2019 Aug 12;8:e47163. doi: 10.7554/eLife.47163.
Irene Bolea  # 1 2,  Alejandro Gella  # 2 3,  Elisenda Sanz  # 2 4 5,  Patricia Prada-Dacasa 2 5,  Fabien Menardy 2,  Angela M Bard 4,  Pablo Machuca-Márquez 2,  Abel Eraso-Pichot 2,  Guillem Mòdol-Caballero 2 5 6,  Xavier Navarro 2 5 6,  Franck Kalume 4 7 8,  Albert Quintana 1 2 4 5 9
Affiliations

Affiliations

  • 1 Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, United States.
  • 2 Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain.
  • 3 Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.
  • 4 Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.
  • 5 Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra, Spain.
  • 6 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.
  • 7 Department of Neurological Surgery, University of Washington, Seattle, United States.
  • 8 Department of Pharmacology, University of Washington, Seattle, United States.
  • 9 Department of Pediatrics, University of Washington, Seattle, United States.
  • # Contributed equally.
PMID: 31403401 DOI: 10.7554/eLife.47163
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.

Keywords

cell type-specific; mitochondrial disease; mouse; mouse genetics; neuropathology; neuroscience.

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