title: Disrupting MLC1 and GlialCAM and ClC-2 interactions in leukodystrophy entails glial chloride channel dysfunction.
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.
authors.affiliation: 1] Leibniz-Institut für molekulare Pharmakologie (FMP), Department Physiology and Pathology of Ion Transport, D-13125 Berlin, Germany [2] Max-Delbrück-Centrum für Molekulare Medizin (MDC), D-13125 Berlin, Germany [3].
authors.forename: Maja B
authors.initials: MB
authors.lastname: Hoegg-Beiler
authors.affiliation: 1] Physiology Section, Physiological Sciences II, Universitat de Barcelona, E-08907 Barcelona, Spain [2] Molecular Genetics Laboratory-IDIBELL, E-08908 Barcelona, Spain [3].
authors.forename: Sònia
authors.initials: S
authors.lastname: Sirisi
authors.affiliation: 1] Leibniz-Institut für molekulare Pharmakologie (FMP), Department Physiology and Pathology of Ion Transport, D-13125 Berlin, Germany [2] Max-Delbrück-Centrum für Molekulare Medizin (MDC), D-13125 Berlin, Germany [3].
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Orozco
authors.affiliation: Institute of Neuropathology, Pathologic Anatomy Service, IDIBELL-University Hospital Bellvitge, E-08907 L'Hospitalet de Llobregat, Spain.
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.affiliation: Leibniz-Institut für molekulare Pharmakologie (FMP), Department Physiology and Pathology of Ion Transport, D-13125 Berlin, Germany.
authors.forename: Svea
authors.initials: S
authors.lastname: Hohensee
authors.affiliation: 1] Leibniz-Institut für molekulare Pharmakologie (FMP), Department Physiology and Pathology of Ion Transport, D-13125 Berlin, Germany [2] Max-Delbrück-Centrum für Molekulare Medizin (MDC), D-13125 Berlin, Germany [3].
authors.forename: Muriel
authors.initials: M
authors.lastname: Auberson
authors.affiliation: 1] Leibniz-Institut für molekulare Pharmakologie (FMP), Department Physiology and Pathology of Ion Transport, D-13125 Berlin, Germany [2] Max-Delbrück-Centrum für Molekulare Medizin (MDC), D-13125 Berlin, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Gödde
authors.affiliation: Molecular Genetics Laboratory-IDIBELL, E-08908 Barcelona, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Vilches
authors.affiliation: 1] Molecular Genetics Laboratory-IDIBELL, E-08908 Barcelona, Spain [2] Centro de Investigación en Red de Enfermedades Raras CIBERER, ISCIII U-730, E-08908 Barcelona, Spain.
authors.forename: Miguel López
authors.initials: ML
authors.lastname: de Heredia
authors.affiliation: 1] Molecular Genetics Laboratory-IDIBELL, E-08908 Barcelona, Spain [2] Centro de Investigación en Red de Enfermedades Raras CIBERER, ISCIII U-730, E-08908 Barcelona, Spain [3] Genetics Section, Physiological Sciences II, Universitat de Barcelona, E-08907 Barcelona, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Nunes
authors.affiliation: 1] Physiology Section, Physiological Sciences II, Universitat de Barcelona, E-08907 Barcelona, Spain [2] Centro de Investigación en Red de Enfermedades Raras CIBERER, ISCIII U-750, E-08907 Barcelona, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: Estévez
authors.affiliation: 1] Leibniz-Institut für molekulare Pharmakologie (FMP), Department Physiology and Pathology of Ion Transport, D-13125 Berlin, Germany [2] Max-Delbrück-Centrum für Molekulare Medizin (MDC), D-13125 Berlin, Germany [3] NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, D-10117 Berlin, Germany.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Jentsch
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D000090007:CLC-2 Chloride Channels; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D019062:Cell Adhesion Molecules, Neuron-Glia / Q000235:genetics / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D056784:Leukoencephalopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018408:Patch-Clamp Techniques
chemical_list: D000090007:CLC-2 Chloride Channels; D015815:Cell Adhesion Molecules; D019062:Cell Adhesion Molecules, Neuron-Glia; D018118:Chloride Channels; C000593181:GlialCAM protein, mouse; D008565:Membrane Proteins; C498927:Mlc1 protein, mouse; D009419:Nerve Tissue Proteins