Disrupting MLC1 and GlialCAM and ClC-2 interactions in leukodystrophy entails glial chloride channel dysfunction.
Nat Commun
; 5: 3475, 2014 Mar 19.
Article
em En
| MEDLINE
| ID: mdl-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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Moléculas de Adesão Celular
/
Canais de Cloreto
/
Moléculas de Adesão Celular Neurônio-Glia
/
Leucoencefalopatias
/
Proteínas de Membrana
/
Proteínas do Tecido Nervoso
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article