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Title: Disrupting MLC1 and GlialCAM and ClC-2interactions in leukodystrophy entails glial chloridechannel dysfunction
Author: 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.
Keywords: Malalties cerebrals
Teixit nerviós
Metabolisme cel·lular
Proteïnes de membrana
Canals de clorur
Brain diseases
Nerve tissue
Cell metabolism
Membrane proteins
Chloride channels
Issue Date: 2014
Publisher: Nature Publishing Group
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.
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It is part of: Nature Communications, 2014, vol. 5, p. 3475
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ISSN: 2041-1723
Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Ciències Fisiològiques)

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