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

Alice Gilbert (1) , Xabier Elorza-Vidal (1) , Armelle Rancillac (1) , Audrey Chagnot (2) , Mervé Yetim (2) , Vincent Hingot (3) , Thomas Deffieux (3) , Anne-Cécile Boulay (1) , Rodrigo Alvear-Perez (1) , Salvatore Cisternino (4) , Sabrina Martin (1) , Sonia Taib (1) , Antoinette Gelot (5) , Virginie Mignon (6) , Maryline Favier (7) , Isabelle Brunet (1) , Xavier Declèves (4) , Mickael Tanter (3) , Raul Estevez (8) , Denis Vivien (2) , Bruno Saubaméa (6) , Martine Cohen-Salmon (1)

1 CIRB - Centre interdisciplinaire de recherche en biologie
2 UNICAEN - Université de Caen Normandie
3 PhysMed Paris - Physique pour la médecine
4 OPTeN (UMR_S 1144 / U1144) - Optimisation thérapeutique en Neuropsychopharmacologie
5 Hôpital Trousseau
6 P-MIM - UMS 3612 - Plates-formes mutualisées du centre de recherche pharmaceutique de Paris
7 IC UM3 (UMR 8104 / U1016) - Institut Cochin
8 University of Barcelona

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.

Mots clés: mouse; neuroscience

Domaines: Neurosciences [q-bio.NC]

Alice Gilbert, Xabier Elorza-Vidal, Armelle Rancillac, Audrey Chagnot, Mervé Yetim, et al.. Megalencephalic leukoencephalopathy with subcortical cysts is a developmental disorder of the gliovascular unit. eLife, 2021, 10, ⟨10.7554/eLife.71379⟩. ⟨hal-03425460⟩