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

Neurobiology of Disease
Angela LanciottiElena Ambrosini

Abstract

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 traffic...Continue Reading

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Citations

Jun 1, 2011·Human Molecular Genetics·Tania López-HernándezRaúl Estévez
Nov 14, 2012·BMC Genomics·Alexandre KuhnAndrew B Singleton
Nov 11, 2014·Annals of Neurology·Mohit DubeyMarjo S van der Knaap
Dec 18, 2013·Translational Neuroscience·Angela LanciottiElena Ambrosini
Mar 29, 2011·Neurobiology of Disease·Anna DuarriRaúl Estévez
Jul 16, 2013·Molecular and Cellular Neurosciences·Stefania PetriniLuisa Bracci-Laudiero
Aug 15, 2017·Brain Pathology·Alexei VerkhratskyVladimir Parpura
Jul 12, 2017·Annals of Clinical and Translational Neurology·Marianna BugianiMarjo S van der Knaap
Feb 9, 2021·Frontiers in Cellular Neuroscience·Assumpció Bosch, Raúl Estévez

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