Disrupting MLC1 and GlialCAM and ClC-2 interactions in leukodystrophy entails glial chloride channel dysfunction

Maja B Hoegg-Beiler; Sònia Sirisi; Ian J Orozco; Isidre Ferrer; Svea Hohensee; Muriel Auberson; Kathrin Gödde; Clara Vilches; Miguel López de Heredia; Virginia Nunes; Raúl Estévez; Thomas J Jentsch

doi:10.1038/ncomms4475

Disrupting MLC1 and GlialCAM and ClC-2 interactions in leukodystrophy entails glial chloride channel dysfunction

Nat Commun. 2014 Mar 19:5:3475. doi: 10.1038/ncomms4475.

Authors

Affiliations

¹ 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].
² 1] Physiology Section, Physiological Sciences II, Universitat de Barcelona, E-08907 Barcelona, Spain [2] Molecular Genetics Laboratory-IDIBELL, E-08908 Barcelona, Spain [3].
³ Institute of Neuropathology, Pathologic Anatomy Service, IDIBELL-University Hospital Bellvitge, E-08907 L'Hospitalet de Llobregat, Spain.
⁴ Leibniz-Institut für molekulare Pharmakologie (FMP), Department Physiology and Pathology of Ion Transport, D-13125 Berlin, Germany.
⁵ 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.
⁶ Molecular Genetics Laboratory-IDIBELL, E-08908 Barcelona, Spain.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ 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.

PMID: 24647135
DOI: 10.1038/ncomms4475

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Astrocytes / metabolism
Astrocytes / pathology
Astrocytes / ultrastructure
Blotting, Western
Brain / metabolism
Brain / pathology
CLC-2 Chloride Channels
Cell Adhesion Molecules / genetics
Cell Adhesion Molecules / metabolism*
Cell Adhesion Molecules, Neuron-Glia / genetics
Cell Adhesion Molecules, Neuron-Glia / metabolism*
Cerebellum / metabolism
Cerebellum / pathology
Chloride Channels / genetics
Chloride Channels / metabolism*
Disease Models, Animal
Female
HEK293 Cells
HeLa Cells
Humans
Leukoencephalopathies / genetics
Leukoencephalopathies / metabolism*
Leukoencephalopathies / pathology
Membrane Potentials
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Confocal
Microscopy, Electron
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
Oligodendroglia / metabolism
Oligodendroglia / pathology
Oligodendroglia / ultrastructure
Patch-Clamp Techniques

Substances

CLC-2 Chloride Channels
Cell Adhesion Molecules
Cell Adhesion Molecules, Neuron-Glia
Chloride Channels
GlialCAM protein, mouse
Membrane Proteins
Mlc1 protein, mouse
Nerve Tissue Proteins