Referenced in: none

Automatically associated channels: ClC2 , ClC4

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

Authors: Maja B Hoegg-Beiler, Sònia Sirisi, Ian J Orozco, Isidre Ferrer, Svea Hohensee, Muriel Auberson, Kathrin Gödde, Clara Vilches, Miguel López de Heredia, Virginia Nunes, Raúl Estévez, Thomas J Jentsch

Journal, date & volume: Nat Commun, 2014 , 5, 3475

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24647135

Abstract
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.