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

Author

Listed:
  • Maja B. Hoegg-Beiler

    (Leibniz-Institut für molekulare Pharmakologie (FMP)
    Max-Delbrück-Centrum für Molekulare Medizin (MDC))

  • Sònia Sirisi

    (Physiology Section, Physiological Sciences II, Universitat de Barcelona
    Molecular Genetics Laboratory-IDIBELL)

  • Ian J. Orozco

    (Leibniz-Institut für molekulare Pharmakologie (FMP)
    Max-Delbrück-Centrum für Molekulare Medizin (MDC))

  • Isidre Ferrer

    (Institute of Neuropathology, Pathologic Anatomy Service, IDIBELL-University Hospital Bellvitge, E-08907 L'Hospitalet de Llobregat, Spain)

  • Svea Hohensee

    (Leibniz-Institut für molekulare Pharmakologie (FMP))

  • Muriel Auberson

    (Leibniz-Institut für molekulare Pharmakologie (FMP)
    Max-Delbrück-Centrum für Molekulare Medizin (MDC)
    Present address: Département de Pharmacologie et Toxicologie, Université de Lausanne, CH-1005 Lausanne, Switzerland)

  • Kathrin Gödde

    (Leibniz-Institut für molekulare Pharmakologie (FMP)
    Max-Delbrück-Centrum für Molekulare Medizin (MDC))

  • Clara Vilches

    (Molecular Genetics Laboratory-IDIBELL)

  • Miguel López de Heredia

    (Molecular Genetics Laboratory-IDIBELL
    Centro de Investigación en Red de Enfermedades Raras CIBERER)

  • Virginia Nunes

    (Molecular Genetics Laboratory-IDIBELL
    Centro de Investigación en Red de Enfermedades Raras CIBERER
    Genetics Section, Physiological Sciences II, Universitat de Barcelona)

  • Raúl Estévez

    (Physiology Section, Physiological Sciences II, Universitat de Barcelona
    Centro de Investigación en Red de Enfermedades Raras CIBERER)

  • Thomas J. Jentsch

    (Leibniz-Institut für molekulare Pharmakologie (FMP)
    Max-Delbrück-Centrum für Molekulare Medizin (MDC)
    NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin)

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.

Suggested Citation

  • 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, 2014. "Disrupting MLC1 and GlialCAM and ClC-2 interactions in leukodystrophy entails glial chloride channel dysfunction," Nature Communications, Nature, vol. 5(1), pages 1-16, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4475
    DOI: 10.1038/ncomms4475
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    Cited by:

    1. Shijie Jin & Xuan Chen & Yang Tian & Rachel Jarvis & Vanessa Promes & Yongjie Yang, 2023. "Astroglial exosome HepaCAM signaling and ApoE antagonization coordinates early postnatal cortical pyramidal neuronal axon growth and dendritic spine formation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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