Megalencephalic leukoencephalopathy with subcortical cysts is a developmental disorder of the gliovascular unit

Abstract

Absence of the astrocyte-specific membrane protein MLC1 is responsible for megalencephalic leukoencephalopathy with subcortical cysts (MLC), a rare type of leukodystrophy characterized by early-onset macrocephaly and progressive white matter vacuolation that lead to ataxia, spasticity, and cognitive decline. During postnatal development (from P5 to P15 in the mouse), MLC1 forms a membrane complex with GlialCAM (another astrocytic transmembrane protein) at the junctions between perivascular astrocytic processes. Perivascular astrocytic processes along with blood vessels form the gliovascular unit. It was not previously known how MLC1 influences the physiology of the gliovascular unit. Here, using the Mlc1 knock-out (KO) mouse model of MLC, we demonstrated that MLC1 controls the postnatal development and organization of perivascular astrocytic processes, vascular smooth muscle cell contractility, neurovascular coupling and intraparenchymal interstitial fluid clearance. Our data suggest that MLC is a developmental disorder of the gliovascular unit, and perivascular astrocytic processes and vascular smooth muscle cell maturation defects are primary events in the pathogenesis of MLC and therapeutic targets for this disease.

Data availability

All data has been included in the manuscript and supporting files (please see supplementary tables for raw data).

Article and author information

Author details

  1. Alice Gilbert

    Collège de France, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Xabier Elorza-Vidal

    Collège de France, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Armelle Rancillac

    Collège de France, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1085-5929
  4. Audrey Chagnot

    GIP Cyceron, Caen, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Mervé Yetim

    GIP Cyceron, CAEN, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Vincent Hingot

    ESPCI, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Thomas Deffieux

    ESPCI, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Anne-Cécile Boulay

    Collège de France, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5620-6209
  9. Rodrigo Alvear-Perez

    Collège de France, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Salvatore Cisternino

    Faculté de pharmacie INSERM UMRS1144, University of Paris, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8500-3574
  11. Sabrina Martin

    Collège de France, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  12. Sonia Taïb Taïb

    Collège de France, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9981-5204
  13. Aontoinette Gelot

    Hopital Trousseau, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  14. Virginie Mignon

    US25 INSERM, UMS3612 CNRS, Faculty of Pharmacy, University of Paris, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  15. Maryline Favier

    Institut Cochin, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  16. Isabelle Brunet

    Collège de France, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5490-2937
  17. Xavier Declèves

    UMR-S 1144, University of Paris, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  18. Mickael Tanter

    ESPCI, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  19. Raul Estevez

    Ciències Fisiològiques II, University of Barcelona, L'Hospitalet de Llobregat, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1579-650X
  20. Denis Vivien

    SP2U, INSERM U919, CAEN, France
    Competing interests
    The authors declare that no competing interests exist.
  21. Bruno Saubaméa

    UMR-S 1144, University of Paris, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  22. Martine Cohen-Salmon

    Collège de France, Paris, France
    For correspondence
    martine.cohen-salmon@college-de-france.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5312-8476

Funding

Association Européenne contre les Leucodystrophies (ELA2012-014C2B)

  • Martine Cohen-Salmon

Fondation Maladies Rares (20170603)

  • Martine Cohen-Salmon

Fondation pour la Recherche Médicale (PLP20170939025p60)

  • Alice Gilbert

Fondation pour la Recherche Médicale (AJE20171039094)

  • Martine Cohen-Salmon

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 animal experiments were carried out in compliance with the European Directive 2010/63/EU on the protection of animals used for scientific purposes and the guidelines issued by the French National Animal Care and Use Committee (reference: 2019021814073504 and 2019022113258393).

Human subjects: Our study included specimens obtained from the brain collection "Hôpitaux Universitaires de l'Est Parisien - Neuropathologie du développement" (Biobank identification number BB-0033-00082). Informed consent was obtained for autopsy of the brain and histological examination.

Copyright

© 2021, Gilbert 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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  1. Alice Gilbert
  2. Xabier Elorza-Vidal
  3. Armelle Rancillac
  4. Audrey Chagnot
  5. Mervé Yetim
  6. Vincent Hingot
  7. Thomas Deffieux
  8. Anne-Cécile Boulay
  9. Rodrigo Alvear-Perez
  10. Salvatore Cisternino
  11. Sabrina Martin
  12. Sonia Taïb Taïb
  13. Aontoinette Gelot
  14. Virginie Mignon
  15. Maryline Favier
  16. Isabelle Brunet
  17. Xavier Declèves
  18. Mickael Tanter
  19. Raul Estevez
  20. Denis Vivien
  21. Bruno Saubaméa
  22. Martine Cohen-Salmon
(2021)
Megalencephalic leukoencephalopathy with subcortical cysts is a developmental disorder of the gliovascular unit
eLife 10:e71379.
https://doi.org/10.7554/eLife.71379

Share this article

https://doi.org/10.7554/eLife.71379

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