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); 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.

Mlc1-Expressing Perivascular Astrocytes Promote Blood–Brain Barrier Integrity

“…Mlc1 À/À mice display neurologic pathologies that have some similarities to early stage MLC in humans (Dubey et al, 2015), although Mlc1 À/À mice do not fully recapitulate the complex brain pathologies that typify the human disease (Hoegg-Beiler et al, 2014). A recent study has reported normal BBB integrity in Mlc1 À/À mice (Gilbert et al, 2021). In the PA-ablated mouse model we describe here, we detect more severe neurologic deficits than those described in Mlc1 À/À mice.…”

“…Also note the close juxtaposition of YFP 1 PAs and Iba1 1 microglia. pathologies found in Mlc1 À/À mice (Gilbert et al, 2021) and in humans with MLC1 mutations (Dubey et al, 2018). Nonetheless, it will be important to determine whether there are other brain pathologies resulting from Mlc1 1 astrocyte ablation that are independent of BBB disruption.…”

HepaCAM Suppresses Glioblastoma Stem Cell Invasion in the Brain

“…HepaCAM in the liver suppresses the growth of hepatocytes and is down-regulated in hepatocellular carcinoma, suggesting tumor suppressor-like functions (2). In the brain, hepaCAM is normally expressed in astrocytes where it regulates ion homeostasis (3), BBB physiology (4), and synaptic excitation (5). Putative functions for hepaCAM in the brain were discovered during genomic sequencing of patients with the neurodevelopmental brain disorder megalencephalic leukoencephalopathy with subcortical cysts (MLC) (6).…”