Megalencephalic leukoencephalopathy with subcortical cysts is a developmental disorder of the gliovascular unit
Alice Gilbert,
Xabier Elorza-Vidal,
Armelle Rancillac,
Audrey Chagnot,
Mervé Yetim,
Vincent Hingot,
Thomas Deffieux,
Anne-Cécile Boulay,
Rodrigo Alvear-Perez,
Salvatore Cisternino,
Sabrina Martin,
Sonia Taïb,
Aontoinette Gelot,
Virginie Mignon,
Maryline Favier,
Isabelle Brunet,
Xavier Declèves,
Mickael Tanter,
Raul Estevez,
Denis Vivien,
Bruno Saubaméa,
Martine Cohen-Salmon
Affiliations
Alice Gilbert
Physiology and Physiopathology of the Gliovascular Unit Research Group, Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS Research in Biology (CIRB), College de France, CNRS, Paris, France; École doctorale Cerveau Cognition Comportement “ED3C” N°158, Pierre and Marie Curie University, Paris, France
Xabier Elorza-Vidal
Physiology and Physiopathology of the Gliovascular Unit Research Group, Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS Research in Biology (CIRB), College de France, CNRS, Paris, France
Neuroglial Interactions in Cerebral Physiopathology Research Group, Center for Interdisciplinary Research in Biology (CIRB), College de France, Labex Memolife, Université PSL, Paris, France
Audrey Chagnot
Normandie University, UNICAEN, INSERM, GIP Cyceron, Institut Blood and Brain, Physiopathology and Imaging of Neurological Disorders, Caen, France
Mervé Yetim
Normandie University, UNICAEN, INSERM, GIP Cyceron, Institut Blood and Brain, Physiopathology and Imaging of Neurological Disorders, Caen, France
Vincent Hingot
Physics for Medicine Paris, ESPCI Paris, PSL University, Paris, France
Thomas Deffieux
Physics for Medicine Paris, ESPCI Paris, PSL University, Paris, France
Physiology and Physiopathology of the Gliovascular Unit Research Group, Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS Research in Biology (CIRB), College de France, CNRS, Paris, France
Rodrigo Alvear-Perez
Physiology and Physiopathology of the Gliovascular Unit Research Group, Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS Research in Biology (CIRB), College de France, CNRS, Paris, France
Université de Paris, Faculté de Santé, Paris, France
Sabrina Martin
Molecular Control of the Neurovascular Development Research Group, Center for Interdisciplinary Research in Biology (CIRB), College de France, Labex Memolife, Université PSL, Paris, France
Molecular Control of the Neurovascular Development Research Group, Center for Interdisciplinary Research in Biology (CIRB), College de France, Labex Memolife, Université PSL, Paris, France
Aontoinette Gelot
Service d’anatomie et cytologie pathologie de l’hôpital Armand Trousseau, Paris, France
Virginie Mignon
Cellular and Molecular Imaging Facility, US25 INSERM, UMS3612 CNRS, Faculty of Pharmacy, University of Paris, Paris, France
Molecular Control of the Neurovascular Development Research Group, Center for Interdisciplinary Research in Biology (CIRB), College de France, Labex Memolife, Université PSL, Paris, France
Xavier Declèves
Université de Paris, Faculté de Santé, Paris, France; Biologie du médicament et toxicologie, Assistance Publique – hôpitaux de Paris, APHP, Hôpital Cochin, Paris, France
Mickael Tanter
Physics for Medicine Paris, ESPCI Paris, PSL University, Paris, France
Unitat de Fisiología, Departament de Ciències Fisiològiques, IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain; Centro de Investigación en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
Denis Vivien
Normandie University, UNICAEN, INSERM, GIP Cyceron, Institut Blood and Brain, Physiopathology and Imaging of Neurological Disorders, Caen, France
Bruno Saubaméa
Université de Paris, Faculté de Santé, Paris, France; Cellular and Molecular Imaging Facility, US25 INSERM, UMS3612 CNRS, Faculty of Pharmacy, University of Paris, Paris, France
Physiology and Physiopathology of the Gliovascular Unit Research Group, Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS Research in Biology (CIRB), College de France, CNRS, Paris, France
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 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.
