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), 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.

MLC1: A New Calcium-regulated Protein Conferring Calcium Dependence to Volume-regulated Anion Channels (VRAC) in Astrocytes.

“…Thus, we cannot exclude that alterations of Ca 2+ dynamics in astrocyte end-feet due to MLC1 mutations might indirectly influence arteriolar dilation and water permeability at the BBB causing edema and NVU dysfunctions. In accordance with this hypothesis, a recent study provide evidence of alterations of vascular smooth muscle cell contractility and NVU coupling in MLC1 KO mice [86].…”

The CaMKII/MLC1 Axis Confers Ca2+-Dependence to Volume-Regulated Anion Channels (VRAC) in Astrocytes

“…Thus, we cannot exclude that alterations of Ca 2+ dynamics in astrocyte end-feet due to MLC1 mutations might influence arteriolar contractility and BBB permeability, causing edema and NVU dysfunctions. In accordance with this hypothesis, a recent study provided evidence of alterations of vascular smooth muscle contractility and NVU coupling in MLC1 KO mice [ 64 ]. The emerging role of MLC1 in the maintenance of BBB/NVU integrity has also been recently highlighted in an elegant in vivo study by Morales and collaborators [ 65 ], who generated and characterized transgenic mice where inducible and selective ablation of perivascular astrocytes expressing MLC1 (but not of other astrocyte populations) could be obtained.…”

GPR37 Receptors and Megalencephalic Leukoencephalopathy with Subcortical Cysts

“…It has been determined that MLC1 might play a role in contractile maturation of vascular smooth muscle cells, arterial perfusion, and neurovascular coupling. Its absence disturbs the postnatal acquisition of contractile properties by vascular smooth muscle cells and disrupts blood perfusion, vessel diameter and neurovascular coupling [ 50 ]. Thus, not only affecting different ion channels and transporters in astrocytes can cause water increase and it might be that disruption of gliovascular unit by itself might contribute also to the increase in water content and seizures observed in MLC patients.…”