Open AccessLocalization and functional analyses of the MLC1 protein involved in megalencephalic leukoencephalopathy with subcortical cysts
Author(s) -
Óscar Teijido,
Albert Martı́nez,
Michael Pusch,
António Zorzano,
Eduardo Soriano,
José Antonio del Rı́o,
Manuel Palacı́n,
Raúl Estévez
Publication year - 2004
Publication title -
human molecular genetics online/human molecular genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.811
H-Index - 276
eISSN - 1460-2083
pISSN - 0964-6906
DOI - 10.1093/hmg/ddh291
Subject(s) - biology , astrocyte , in situ hybridization , microbiology and biotechnology , neuroglia , glial fibrillary acidic protein , pathology , central nervous system , gene expression , immunohistochemistry , gene , neuroscience , genetics , immunology , medicine
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 Ca(2+)-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.