Hoegg-Beiler, Maja B.Sirisi Dolcet, SòniaOrozco, Ian J.Ferrer, Isidro (Ferrer Abizanda)Hohensee, SveaAuberson, MurielGödde, KathrinVilches, ClaraLópez de Heredia, MiguelNunes Martínez, VirginiaEstévez Povedano, RaúlJentsch, Thomas J.2019-02-282019-02-2820142041-1723https://hdl.handle.net/2445/129370Defects 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.17 p.application/pdfengcc-by (c) Hoegg-Beiler, Maja B. et al., 2014http://creativecommons.org/licenses/by/3.0/esMalalties cerebralsTeixit nerviósMetabolisme cel·lularProteïnes de membranaCanals de clorurBrain diseasesNerve tissueCell metabolismMembrane proteinsChloride channelsinfo:eu-repo/semantics/article6362662019-02-28info:eu-repo/semantics/openAccess24647135