Disrupting MLC1 and GlialCAM and ClC-2 interactions in leukodystrophy entails glial chloride channel dysfunction

• DOI: 10.1038/ncomms4475
• Publication Date: 2014-03-19T13:39:52Z
• Authors: Maja B. Hoegg-Beiler; Sònia Sirisi; Ian J. Orozco; Isidre Ferrer; Svea Hohensee; Muriel Auberson; Kathrin Gödde; Clara Vilches; Miguel López de H...; Virginia Nunes; Raúl Estévez; Thomas J. Jentsch
• Keywords: 0301 basic medicine; Blotting, Western; Malalties cerebrals; Metabolisme cel·lular; Membrane Potentials; Mice; 03 medical and health sciences; Chloride Channels; Leukoencephalopathies; Cerebellum; Membrane proteins; Animals; Humans; Nerve tissue; Chloride channels; Mice, Knockout; Cell metabolism; 0303 health sciences; Teixit nerviós; Cell Adhesion Molecules, Neuron-Glia; Proteïnes de membrana; Brain; Membrane Proteins; Canals de clorur; CLC-2 Chloride Channels; Mice, Inbred C57BL; Disease Models, Animal; HEK293 Cells; Cardiovascular and Metabolic Diseases; Astrocytes; Female; Brain diseases; Function and Dysfunction of the Nervous System; Cell Adhesion Molecules; HeLa Cells

Defects in the astrocytic membrane protein MLC1, the adhesion molecule GlialCAM or the chloride channel ClC-2 underlie human leukoencephalopathies. Whereas GlialCAM binds ClC-2 and MLC1, and modifies ClC-2 currents in vitro, no functional connections between MLC1 and ClC-2 are known. Here we investigate this by generating loss-of-function Glialcam and Mlc1 mouse models manifesting myelin vacuolization. We find that ClC-2 is unnecessary for MLC1 and GlialCAM localization in brain, whereas GlialCAM is important for targeting MLC1 and ClC-2 to specialized glial domains in vivo and for modifying ClC-2's biophysical properties specifically in oligodendrocytes (OLs), the cells chiefly affected by vacuolization. Unexpectedly, MLC1 is crucial for proper localization of GlialCAM and ClC-2, and for changing ClC-2 currents. Our data unmask an unforeseen functional relationship between MLC1 and ClC-2 in vivo, which is probably mediated by GlialCAM, and suggest that ClC-2 participates in the pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts.