Journal Article

Regulation of glycogen synthesis by the laforin–malin complex is modulated by the AMP-activated protein kinase pathway

Maria Carmen Solaz-Fuster, José Vicente Gimeno-Alcañiz, Susana Ros, Maria Elena Fernandez-Sanchez, Belen Garcia-Fojeda, Olga Criado Garcia, David Vilchez, Jorge Dominguez, Mar Garcia-Rocha, Maribel Sanchez-Piris, Carmen Aguado, Erwin Knecht, Jose Serratosa, Joan Josep Guinovart, Pascual Sanz and Santiago Rodriguez de Córdoba

in Human Molecular Genetics

Volume 17, issue 5, pages 667-678
Published in print March 2008 | ISSN: 0964-6906
Published online November 2007 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddm339
Regulation of glycogen synthesis by the laforin–malin complex is modulated by the AMP-activated protein kinase pathway

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Lafora progressive myoclonus epilepsy (LD) is a fatal autosomal recessive neurodegenerative disorder characterized by the presence of glycogen-like intracellular inclusions called Lafora bodies. LD is caused by mutations in two genes, EPM2A and EPM2B, encoding respectively laforin, a dual-specificity protein phosphatase, and malin, an E3 ubiquitin ligase. Previously, we and others have suggested that the interactions between laforin and PTG (a regulatory subunit of type 1 protein phosphatase) and between laforin and malin are critical in the pathogenesis of LD. Here, we show that the laforin–malin complex downregulates PTG-induced glycogen synthesis in FTO2B hepatoma cells through a mechanism involving ubiquitination and degradation of PTG. Furthermore, we demonstrate that the interaction between laforin and malin is a regulated process that is modulated by the AMP-activated protein kinase (AMPK). These findings provide further insights into the critical role of the laforin–malin complex in the control of glycogen metabolism and unravel a novel link between the energy sensor AMPK and glycogen metabolism. These data advance our understanding of the functional role of laforin and malin, which hopefully will facilitate the development of appropriate LD therapies.

Journal Article.  7236 words.  Illustrated.

Subjects: Genetics and Genomics

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