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

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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].
      Authors
    • Hoegg-Beiler MB 1
    • Orozco IJ 1
    • Auberson M 1
    (3 authors)
  • 2. 1] Physiology Section, Physiological Sciences II, Universitat de Barcelona, E-08907 Barcelona, Spain [2] Molecular Genetics Laboratory-IDIBELL, E-08908 Barcelona, Spain [3].
      Authors
    • Sirisi S 2
    (1 author)
  • 3. Institute of Neuropathology, Pathologic Anatomy Service, IDIBELL-University Hospital Bellvitge, E-08907 L'Hospitalet de Llobregat, Spain.
      Authors
    • Ferrer I 3
    (1 author)
  • 4. Leibniz-Institut für molekulare Pharmakologie (FMP), Department Physiology and Pathology of Ion Transport, D-13125 Berlin, Germany.
      Authors
    • Hohensee S 4
    (1 author)
  • 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.
      Authors
    • Gödde K 5
    (1 author)
    • Show all (10)

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Nature Communications, 19 Mar 2014, 5:3475
https://doi.org/10.1038/ncomms4475 PMID: 24647135 

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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