RT Journal Article SR Electronic T1 Megalencephalic leukoencephalopathy with subcortical cysts is a developmental disorder of the gliovascular unit JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.05.17.444434 DO 10.1101/2021.05.17.444434 A1 Alice Gilbert A1 Xabier Elorza-Vidal A1 Armelle Rancillac A1 Audrey Chagnot A1 Mervé Yetim A1 Vincent Hingot A1 Thomas Deffieux A1 Anne-Cécile Boulay A1 Rodrigo Alvear-Perez A1 Salvatore Cisternino A1 Sabrina Martin A1 Sonia Taib A1 Antoinette Gelot A1 Virginie Mignon A1 Maryline Favier A1 Isabelle Brunet A1 Xavier Declèves A1 Mickael Tanter A1 Raul Estevez A1 Denis Vivien A1 Bruno Saubaméa A1 Martine Cohen-Salmon YR 2021 UL http://biorxiv.org/content/early/2021/05/17/2021.05.17.444434.abstract AB Absence of the astrocyte-specific membrane protein MLC1 is responsible for megalencephalic leukoencephalopathy with subcortical cysts (MLC); this rare type of leukodystrophy is 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 (PvAPs, which along with blood vessels form the gliovascular unit (GVU)). We analyzed the GVU in the Mlc1 knock-out mouse model of MLC. The absence of MLC1 led to an accumulation of fluid in the brain but did not modify the endothelial organization or the integrity of the blood-brain barrier. From P10 onward, the postnatal acquisition of vascular smooth muscle cell contractility was altered, resulting in a marked reduction in arterial perfusion and neurovascular coupling. These anomalies were correlated with alterations in astrocyte morphology, astrocyte polarity and the structural organization of the PvAP’s perivascular coverage, and poor intraparenchymal circulation of the cerebrospinal fluid (CSF). Hence, MLC1 is required for the postnatal development and organization of PvAPs and controls vessel contractility and intraparenchymal interstitial fluid clearance. Our data suggest that (i) MLC is a developmental disorder of the GVU, and (ii) PvAP and VSMC maturation defects are primary events in the pathogenesis of MLC and therapeutic targets for this disease.Competing Interest StatementThe authors have declared no competing interest.