Title:
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Disrupting MLC1 and GlialCAM and ClC-2interactions in leukodystrophy entails glial chloridechannel dysfunction
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Author:
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Hoegg-Beiler, Maja B.; Sirisi Dolcet, Sònia; Orozco, Ian J.; Ferrer, Isidro (Ferrer Abizanda); Hohensee, Svea; Auberson, Muriel; Gödde, Kathrin; Vilches, Clara; López de Heredia, Miguel; Nunes Martínez, Virginia; Estévez Povedano, Raúl; Jentsch, Thomas J.
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Abstract:
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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. |
Subject(s):
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-Malalties cerebrals -Teixit nerviós -Metabolisme cel·lular -Proteïnes de membrana -Canals de clorur -Brain diseases -Nerve tissue -Cell metabolism -Membrane proteins -Chloride channels |
Rights:
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cc-by (c) Hoegg-Beiler, Maja B. et al., 2014
http://creativecommons.org/licenses/by/3.0/es |
Document type:
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Article Article - Published version |
Published by:
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Nature Publishing Group
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