Insights into MLC pathogenesis: GlialCAM is an MLC1 chaperone required for proper activation of volume-regulated anion currents.

@article{CapdevilaNortes2013InsightsIM,
  title={Insights into MLC pathogenesis: GlialCAM is an MLC1 chaperone required for proper activation of volume-regulated anion currents.},
  author={Xavier Capdevila-Nortes and Tania L{\'o}pez-Hern{\'a}ndez and Pirjo M. Apaja and Miguel L{\'o}pez de Heredia and S{\`o}nia Sirisi and Gerard Callejo and Tanit Arnedo and Virginia Nunes and Gergely L. Lukacs and Xavier Gasull and Ra{\'u}l Est{\'e}vez},
  journal={Human molecular genetics},
  year={2013},
  volume={22 21},
  pages={
          4405-16
        }
}
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy caused by mutations in either MLC1 or GLIALCAM genes and is associated with myelin and astrocyte vacuolation. It has been suggested that MLC is caused by impaired cell volume regulation as a result of defective activation of astrocytic volume-regulated anion currents (VRAC). GlialCAM brings MLC1 and the ClC-2 Cl(-) channel to cell-cell junctions, even though the role of ClC-2 in MLC disease remains… 

Figures from this paper

Disrupting MLC1 and GlialCAM and ClC-2 interactions in leukodystrophy entails glial chloride channel dysfunction.
TLDR
It is suggested that ClC-2 participates in the pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts, and MLC1 is crucial for proper localization of GlialCAM and ClC -2, and for changing Cl C-2 currents.
Megalencephalic leukoencephalopathy with subcortical cysts protein 1 regulates glial surface localization of GLIALCAM from fish to humans.
TLDR
An evolutionary conserved role for MLC1 in regulating glial surface levels of GLialCAM is demonstrated, and this interrelationship explains why patients with mutations in either gene (MLC1 or GLIALCAM) share the same clinical phenotype.
MLC1 protein: a likely link between leukodystrophies and brain channelopathies
TLDR
Evidence linking the effects of MLC1 mutations to brain channelopathies is discussed and data on MLC 1 functional properties obtained in in vitro and in vivo models is reviewed.
Megalencephalic Leukoencephalopathy: Insights Into Pathophysiology and Perspectives for Therapy
TLDR
MLC1 expression in the cerebellum extremely reduced myelin vacuolation at all ages in a dose-dependent manner and could be considered as the first preclinical approach for MLC.
Structural basis for the dominant or recessive character of GLIALCAM mutations found in leukodystrophies
TLDR
A combination of biochemistry methods with a new developed anti-GlialCAM nanobody, double-mutants and cysteine cross-links experiments, together with computer docking, are used to create a structural model of GlIALCAM homo-interactions to provide a framework that can be used to understand the molecular basis of pathogenesis of all identified GLIALCam mutations.
Control of membrane protein homeostasis by a chaperone-like glial cell adhesion molecule at multiple subcellular locations
TLDR
Observations indicate an essential and previously unrecognized role for CAM, where GliaCAM functions as a PQC factor for the MLC1 signalling complex biogenesis and possess a permissive role in the membrane dynamic and cargo sorting functions with implications in modulations of receptor signalling.
Cerebellar Astrocyte Transduction as Gene Therapy for Megalencephalic Leukoencephalopathy
TLDR
The first therapeutic approach for patients affected with MLC is provided, which may have also implications to treat other diseases affecting motor function such as ataxias.
GPR37 Receptors and Megalencephalic Leukoencephalopathy with Subcortical Cysts
TLDR
New aspects of the pathophysiology of MLC disease and key aspect of the interaction between GPR37 receptors and MLC proteins are summarized.
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