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

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Official URL:https://doi.org/10.1038/ncomms4475
PubMed:View item in PubMed
Creators Name:Hoegg-Beiler, M.B. and Sirisi, S. and Orozco, I.J. and Ferrer, I. and Hohensee, S. and Auberson, M. and Goedde, K. and Vilches, C. and de Heredia, M.L. and Nunes, V. and Estevez, R. and Jentsch, T.J.
Journal Title:Nature Communications
Journal Abbreviation:Nat Commun
Volume:5
Page Range:3475
Date:19 March 2014
Keywords:Animal Disease Models, Astrocytes, Brain, Cell Adhesion Molecules, Cerebellum, Chloride Channels, Confocal Microscopy, Electron Microscopy, HEK293 Cells, HeLa Cells, Inbred C57BL Mice, Knockout Mice, Leukoencephalopathies, Membrane Potentials, Membrane Proteins, Nerve Tissue Proteins, Neuron-Glia Cell Adhesion Molecules , Oligodendroglia, Patch-Clamp Techniques, Western Blotting, Animals, Mice
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.
ISSN:2041-1723
Publisher:Nature Publishing Group (U.K.)
Item Type:Article

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