Megalencephalic leukoencephalopathy with subcortical cysts is a developmental disorder of the gliovascular unit
- Collège de France, France
- GIP Cyceron, France
- ESPCI, France
- University of Paris, France
- Hopital Trousseau, France
- Institut Cochin, France
- University of Barcelona, Spain
- INSERM U919, France
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
Anne-Cécile Boulay
Salvatore Cisternino
Martine Cohen-Salmon
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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Megalencephalic leukoencephalopathy with subcortical cysts is a developmental disorder of the gliovascular unit
eLife 10:e71379.
https://doi.org/10.7554/eLife.71379
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