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 () and Thomas J. Jentsch ()
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Maja B. Hoegg-Beiler: Leibniz-Institut für molekulare Pharmakologie (FMP)
Sònia Sirisi: Physiology Section, Physiological Sciences II, Universitat de Barcelona
Ian J. Orozco: Leibniz-Institut für molekulare Pharmakologie (FMP)
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)
Kathrin Gödde: Leibniz-Institut für molekulare Pharmakologie (FMP)
Clara Vilches: Molecular Genetics Laboratory-IDIBELL
Miguel López de Heredia: Molecular Genetics Laboratory-IDIBELL
Virginia Nunes: Molecular Genetics Laboratory-IDIBELL
Raúl Estévez: Physiology Section, Physiological Sciences II, Universitat de Barcelona
Thomas J. Jentsch: Leibniz-Institut für molekulare Pharmakologie (FMP)

Nature Communications, 2014, vol. 5, issue 1, 1-16

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4475

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