MLC1 protein: a likely link between leukodystrophies and brain channelopathies.

Maria S Brignone,Sergio Visentin,Angela Lanciotti,Serena Camerini,Elena Ambrosini,Tamara C Petrucci,Chiara De Nuccio

doi:10.3389/fncel.2015.00106

Abstract

Megalencephalic leukoencephalopathy with subcortical cysts (MLCs) disease is a rare inherited, autosomal recessive form of childhood-onset spongiform leukodystrophy characterized by macrocephaly, deterioration of motor functions, epileptic seizures and mental decline. Brain edema, subcortical fluid cysts, myelin and astrocyte vacuolation are the histopathological hallmarks of MLC. Mutations in either the MLC1 gene (>75% of patients) or the GlialCAM gene (<20% of patients) are responsible for the disease. Recently, the GlialCAM adhesion protein was found essential for the membrane expression and function of the chloride channel ClC-2 indicating MLC disease caused by mutation in GlialCAM as the first channelopathy among leukodystrophies. On the contrary, the function of MLC1 protein, which binds GlialCAM, its functional relationship with ClC-2 and the molecular mechanisms underlying MLC1 mutation-induced functional defects are not fully understood yet. The human MLC1 gene encodes a 377-amino acid membrane protein with eight predicted transmembrane domains which shows very low homology with voltage-dependent potassium (K+) channel subunits. The high expression of MLC1 in brain astrocytes contacting blood vessels and meninges and brain alterations observed in MLC patients have led to hypothesize a role for MLC1 in the regulation of ion and water homeostasis. Recent studies have shown that MLC1 establishes structural and/or functional interactions with several ion/water channels and transporters and ion channel accessory proteins, and that these interactions are affected by MLC1 mutations causing MLC. Here, we review data on MLC1 functional properties obtained in in vitro and in vivo models and discuss evidence linking the effects of MLC1 mutations to brain channelopathies.

Highlights

Channelopathies are a heterogeneous group of disorders of genetic or acquired origin caused by altered function of ion channel subunits or the proteins that regulate them
MLC1 protein structural features, molecular interactors and brain alterations observed in Megalencephalic leukoencephalopathy with subcortical cysts (MLCs) patients suggest that MLC1 can play a role in the regulation of ion and water fluxes and cell volume
Our studies demonstrated that in astrocytes exposed to hyposmotic stress MLC1 is translocated to the plasma membrane and internalized by caveolar endocytosis to be sorted to recycling or degradation pathways (Figure 3)

Summary

Introduction

Channelopathies are a heterogeneous group of disorders of genetic or acquired origin caused by altered function of ion channel subunits or the proteins that regulate them. The identification of GlialCAM as the molecular chaperon and functional modulator of the chloride channel ClC-2 (Jeworutzki et al, 2014) has allowed for the first time to explain the similarities between brain alterations found in ClC-2 KO mice (Blanz et al, 2007) and those characteristic of MLC patients This finding led to identify MLC disease caused by mutations in the GlialCAM gene as the first leukodystrophy among brain channelopathies. MLC1 protein structural features, molecular interactors (see below) and brain alterations observed in MLC patients (edema, fluid cysts, astrocyte, and myelin vacuolation) suggest that MLC1 can play a role in the regulation of ion and water fluxes and cell volume. MLC1 protein was found predominantly in TABLE 1 | Newly identified megalencephalic leukoencephalopathy with subcortical cyst (MLC1) molecular interactors

Accession number

DGC complex

Findings

Experimental models