MLC1 trafficking and membrane expression in astrocytes: role of caveolin-1 and phosphorylation.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare congenital leukodystrophy caused by mutations in the MLC1 gene that encodes a membrane protein of unknown function. In the brain MLC1 protein is mainly expressed in astrocyte end-feet, localizes in lipid rafts and associates with the dystrophin glycoprotein complex (DGC). Using ...
pull-down and co-fractionation assays in cultured human and rat astrocytes, we show here that MLC1 intracellular domains pull-down the DGC proteins syntrophin, dystrobrevin, Kir4.1 and caveolin-1, the structural protein of caveolae, thereby supporting a role for DGC and caveolar structures in MLC1 function. By immunostaining and subcellular fractionation of cultured rat or human astrocytes treated with agents modulating caveolin-mediated trafficking, we demonstrate that MLC1 is also expressed in intracellular vesicles and endoplasmic reticulum and undergoes caveolae/raft-mediated endocytosis. Inhibition of endocytosis, cholesterol lowering and protein kinases A- and C-mediated MLC1 phosphorylation favour the expression of membrane-associated MLC1. Because pathological mutations prevent MLC1 membrane expression, the identification of substances regulating MLC1 intracellular trafficking is potentially relevant for the therapy of MLC.
Mesh Terms:
Animals, Animals, Newborn, Astrocytes, Brain, Caveolae, Caveolin 1, Cell Line, Tumor, Cell Membrane, Cells, Cultured, Cholesterol, Cyclic AMP-Dependent Protein Kinases, Cytoplasmic Vesicles, Dystrophin-Associated Protein Complex, Endocytosis, Endoplasmic Reticulum, Humans, Leukoencephalopathies, Membrane Microdomains, Membrane Proteins, Phosphorylation, Protein Kinase C, Protein Transport, Rats
Neurobiol. Dis.
Date: Mar. 01, 2010
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