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oai:recercat.cat:2445/1293702025-12-05T09:21:31Zcom_2072_1057col_2072_478799col_2072_478916col_2072_478917col_2072_478929

Disrupting MLC1 and GlialCAM and ClC-2interactions in leukodystrophy entails glial chloridechannel dysfunction 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. Malalties cerebrals Teixit nerviós Metabolisme cel·lular Proteïnes de membrana Canals de clorur Brain diseases Nerve tissue Cell metabolism Membrane proteins Chloride channels 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. 2019-02-28T12:51:05Z 2019-02-28T12:51:05Z 2014 2019-02-28T12:51:05Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Reproducció del document publicat a: https://doi.org/10.1038/ncomms4475 Nature Communications, 2014, vol. 5, p. 3475 https://doi.org/10.1038/ncomms4475 cc-by (c) Hoegg-Beiler, Maja B. et al., 2014 http://creativecommons.org/licenses/by/3.0/es info:eu-repo/semantics/openAccess Nature Publishing Group Articles publicats en revistes (Ciències Fisiològiques)