1. Neuroscience
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Defined neuronal populations drive fatal phenotype in a mouse model of Leigh Syndrome

  1. Irene Bolea  Is a corresponding author
  2. Alejandro Gella
  3. Elisenda Sanz
  4. Patricia Prada-Dacasa
  5. Fabien Menardy
  6. Angela M Bard
  7. Pablo Machuca-Márquez
  8. Abel Eraso-Pichot
  9. Guillem Mòdol-Caballero
  10. Xavier Navarro
  11. Franck Kalume
  12. Albert Quintana  Is a corresponding author
  1. Seattle Children's Research Institute, United States
  2. Universitat Autònoma de Barcelona, Spain
Research Article
  • Cited 9
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Cite this article as: eLife 2019;8:e47163 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.

Article and author information

Author details

  1. Irene Bolea

    Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, United States
    For correspondence
    irene.bolea@uab.cat
    Competing interests
    The authors declare that no competing interests exist.
  2. Alejandro Gella

    Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Elisenda Sanz

    Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7932-8556
  4. Patricia Prada-Dacasa

    Institut de Neurociencies, Universitat Autònoma de Barcelona, Bellaterra, Spain
    Competing interests
    The authors declare that no competing interests exist.
  5. Fabien Menardy

    Institut de Neurociencies, Universitat Autònoma de Barcelona, Bellaterra, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8712-1344
  6. Angela M Bard

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Pablo Machuca-Márquez

    Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7980-3839
  8. Abel Eraso-Pichot

    Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain
    Competing interests
    The authors declare that no competing interests exist.
  9. Guillem Mòdol-Caballero

    Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain
    Competing interests
    The authors declare that no competing interests exist.
  10. Xavier Navarro

    Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain
    Competing interests
    The authors declare that no competing interests exist.
  11. Franck Kalume

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5528-2565
  12. Albert Quintana

    Center for Developmental Therapeutics, Seattle Children's Research Institute, Seatle, United States
    For correspondence
    albert.quintana@uab.cat
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1674-7160

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.

Reviewing Editor

  1. Matt Kaeberlein, University of Washington, United States

Publication history

  1. Received: March 26, 2019
  2. Accepted: August 11, 2019
  3. Accepted Manuscript published: August 12, 2019 (version 1)
  4. Version of Record published: September 6, 2019 (version 2)

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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