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Human Molecular Genetics Advance Access published online on November 20, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm339
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Maria del Carmen Solaz-Fuster1,$, José Vicente Gimeno-Alcañiz1,$, Susana Ros2, Maria Elena Fernandez-Sanchez3, Belen Garcia-Fojeda3, Olga Criado Garcia3, David Vilchez2, Jorge Dominguez2, Mar Garcia-Rocha2, Maribel Sanchez-Piris4, Carmen Aguado4, Erwin Knecht4, Jose Serratosa5, Joan Josep Guinovart2, Pascual Sanz1,#,* and Santiago Rodriguez de Córdoba3,#

1 Instituto de Biomedicina de Valencia (Consejo Superior de Investigaciones Científicas), Jaime Roig 11, 46010-Valencia, Spain, and CIBERER-ISCIII, Valencia, Spain 2 Institute for Research in Biomedicine and University of Barcelona, Barcelona Science Park, Josep Samitier 1-5, 08028-Barcelona, Spain 3 Centro de Investigaciones Biologicas (Consejo Superior de Investigaciones Cientificas), Ramiro de Maeztu 9, 28040-Madrid, Spain, and CIBERER-ISCIII, Madrid, Spain 4 Centro de Investigación Principe Felipe, Avda. Autopista del Saler 16, 46013-Valencia, Spain, and CIBERER-ISCIII, Valencia, Spain 5 Servicio Neurologia, Fundación Jimenez Diaz, Avda. Reyes Católicos 2, 28040-Madrid, Spain, and CIBERER-ISCIII, Madrid, Spain

* Correspondence should be addressed to Pascual Sanz, Instituto de Biomedicina de Valencia, CSIC, Jaime Roig 11, 46010-Valencia, Spain Tel. +3496-3391779, FAX. +3496-3690800; sanz{at}ibv.csic.es

Received July 30, 2007; Revised November 17, 2007; Accepted July 17, 2007

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.

$ These authors contributed equally to this work.

# These senior authors contributed equally to this work.


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