Megalencephalic leukoencephalopathy with subcortical cysts protein 1 regulates glial surface localization of GLIALCAM from fish to humans.
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a leukodystrophy characterized by myelin vacuolization and caused by mutations in MLC1 or GLIALCAM. Patients with recessive mutations in either MLC1 or GLIALCAM show the same clinical phenotype. It has been shown that GLIALCAM is necessary for the correct targeting of MLC1 to the membrane at cell junctions, but its own localization was independent of MLC1 in vitro. However, recent studies in Mlc1(-/-) mice have shown that GlialCAM is mislocalized in glial cells. In order to investigate whether the relationship between Mlc1 and GlialCAM is species-specific, we first identified MLC-related genes in zebrafish and generated an mlc1(-/-) zebrafish. We have characterized mlc1(-/-) zebrafish both functionally and histologically and compared the phenotype with that of the Mlc1(-/-) mice. In mlc1(-/-) zebrafish, as in Mlc1(-/-) mice, Glialcam is mislocalized. Re-examination of a brain biopsy from an MLC patient indicates that GLIALCAM is also mislocalized in Bergmann glia in the cerebellum. In vitro, impaired localization of GlialCAM was observed in astrocyte cultures from Mlc1(-/-) mouse only in the presence of elevated potassium levels, which mimics neuronal activity. In summary, here we demonstrate an evolutionary conserved role for MLC1 in regulating glial surface levels of GLIALCAM, and this interrelationship explains why patients with mutations in either gene (MLC1 or GLIALCAM) share the same clinical phenotype.
Sección de Fisiología, Departamento de Ciencias Fisiológicas II, Laboratorio de Genética Molecular-IDIBELL, L'Hospitalet de Llobregat, Spain.
Sònia
S
Sirisi
Department of Cell & Molecular Biology, University of A Coruña, A Coruña, Spain.
Mónica
M
Folgueira
Sección de Fisiología, Departamento de Ciencias Fisiológicas II.
Tania
T
López-Hernández
Department of Pharmacy and Biotecnology, University of Bologna, Bologna, Italy.
Laura
L
Minieri
Sección de Fisiología, Departamento de Ciencias Fisiológicas II.
Carla
C
Pérez-Rius
Sección de Fisiología, Departamento de Ciencias Fisiológicas II.
Héctor
H
Gaitán-Peñas
Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
Jingjing
J
Zang
Department of Cell Biology and.
Albert
A
Martínez
Sección de Fisiología, Departamento de Ciencias Fisiológicas II.
Xavier
X
Capdevila-Nortes
Department of Systems Biology, University of Alcalá, Alcalá de Henares, Madrid, Spain.
Pedro
P
De La Villa
Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands Institute of Medical Physics and Biophysics, University of Leipzig, Leipzig, Germany.
Upasana
U
Roy
Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands Institute of Medical Physics and Biophysics, University of Leipzig, Leipzig, Germany.
A
A
Alia
Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
Stephan
S
Neuhauss
Department of Pharmacy and Biotecnology, University of Bologna, Bologna, Italy.
Stefano
S
Ferroni
Sección de Genética, Departamento de Ciencias Fisiológicas II, Universidad de Barcelona, Barcelona, Spain Laboratorio de Genética Molecular-IDIBELL, L'Hospitalet de Llobregat, Spain U-730 and.
Virginia
V
Nunes
Sección de Fisiología, Departamento de Ciencias Fisiológicas II, U-750, Centro de Investigación en red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain restévez@ub.edu abarrallo@ub.edu.
Raúl
R
Estévez
Sección de Fisiología, Departamento de Ciencias Fisiológicas II, U-750, Centro de Investigación en red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain restévez@ub.edu abarrallo@ub.edu.
Alejandro
A
Barrallo-Gimeno
D000818:Animals; D030801:Animals, Genetically Modified; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003560:Cysts / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004805:Ependyma / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D015870:Gene Expression; D005838:Genotype; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism / Q000648:ultrastructure; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009457:Neuroglia / Q000378:metabolism*; D010641:Phenotype; D021381:Protein Transport; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000378:metabolism; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; C487620:HEPACAM protein, human; C425069:MLC1 protein, human; D008565:Membrane Proteins; D011506:Proteins; D050994:Voltage-Dependent Anion Channels