Journal
HUMAN MOLECULAR GENETICS
Volume 26, Issue 13, Pages 2436-2450Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddx134
Keywords
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Funding
- European Leukodystrophies Association (ELA) Research Foundation [ELA2012-014C2B]
- Ministerio de Ciencia e Innovacion (MICINN) [SAF SAF2012-31486, SAF2015-70377]
- Generalitat de Catalunya [SGR2014-1178, SGR2014-1165, SGR2014-541]
- Instituto de Salud Carlos III: ERARE [FISPI14/00141, FIS PI13/00121, RETIC RD16/0008/0014]
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Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy caused by mutations in either MLC1 or GLIALCAM. GlialCAM is necessary for the correct targeting of MLC1, but also for the targeting of the Cl-channel ClC-2. Furthermore, GlialCAM modifies ClC-2 functional properties in vitro. However, in vivo studies in GlialCAM(-/-)mice have shown that the modification of ClC-2 activity only occurs in oligodendrocytes, despite GlialCAM and ClC-2 being expressed in astrocytes. Thus, the relationship between GlialCAM, MLC1 and ClC-2 in astrocytes is unknown. Here, we show that GlialCAM, ClC-2 and MLC1 can form a ternary complex in cultured astrocytes, but only under depolarizing conditions. We also provide biochemical evidences that this ternary complex exists in vivo. The formation of this complex changes ClC-2 localization in the membrane and its functional properties. ClC-2 association with GlialCAM/MLC1 depends on calcium flux through L-type calcium channels and activation of calcium-dependent calpain proteases. Based on these studies, we propose that the chloride influx mediated by GlialCAM/MLC1/ClC-2 in astrocytes may be needed to compensate an excess of potassium, as occurs in conditions of high neuronal activity. We suggest that a defect in this compensation may contribute to the pathogenesis of MLC disease.
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