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Human Molecular Genetics Advance Access published online on September 14, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh291
© 2004 by Oxford University Press
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Article

Localization and functional analyses of the MLC1 protein involved in megalencephalic leukoencephalopathy with subcortical cysts

Oscar Teijido 1, Albert Martínez 2, Michael Pusch 3, Antonio Zorzano 1, Eduardo Soriano 2, Jose Antonio del Río 2, Manuel Palacín 1, and Raúl Estévez 1*

1 Department of Biochemistry and Molecular Biology, Barcelona Science Park, Josep Samitier 1-5. Barcelona, E-08028, Spain
2 Department of Cell Biology, Faculty of Biology and Barcelona Science Park, Josep Samitier 1-5. Barcelona, E-08028, Spain
3 Istituto di Biofisica, Via de Marini 6, I-16149 Genova, Italy

* To whom correspondence should be addressed. E-mail: restevez{at}pcb.ub.es.


  Abstract

Mutations in the MLC1 gene are responsible for one form of the neurological disorder megalencephalic leukoencephalopathy with subcortical cysts (MLC). The disease is a type of vacuolating myelinopathy. The biochemical properties and the function of the MLC1 protein are unknown. To characterize MLC1, we generated polyclonal antibodies. The MLC1 protein was detected in the brain, assembled into higher molecular complexes, as assessed by assembly-dependent trafficking assays. In situ hybridization and immunohistochemistry were used to determine MLC1 localization within the adult mouse brain. MLC1 was expressed in neurons, detected preferentially in particular axonal tracts. This expression pattern correlates with the major phenotype observed in the disease. In addition, it was expressed in some astrocytes, concentrating in Bergmann glia, the astrocyte end-feet membranes adjacent to blood vessels, and in astrocyte-astrocyte membrane contact regions. Other neuronal barriers, such as the ependyma and the pia mater, were also positive for MLC1 expression. MLC1 was detected in vivo and in heterologous systems at the plasma membrane. MLC mutations impaired folding, and the defect was corrected in vitro by addition of curcumin, a Ca2+-ATPase inhibitor. In summary, this study provides an explanation as to why mutations in MLC1 provoke the disease and points to a possible therapy for some patients.


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A. Duarri, O. Teijido, T. Lopez-Hernandez, G. C. Scheper, H. Barriere, I. Boor, F. Aguado, A. Zorzano, M. Palacin, A. Martinez, et al.
Molecular pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts: mutations in MLC1 cause folding defects
Hum. Mol. Genet., December 1, 2008; 17(23): 3728 - 3739.
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