Human Molecular Genetics Advance Access originally published online on November 20, 2007
Human Molecular Genetics 2008 17(5):667-678; doi:10.1093/hmg/ddm339
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Regulation of glycogen synthesis by the laforin–malin complex is modulated by the AMP-activated protein kinase pathway
,*1 Instituto de Biomedicina de Valencia (Consejo Superior de Investigaciones Científicas), and CIBERER-ISCIII, Jaime Roig 11, Valencia 46010, Spain 2 Institute for Research in Biomedicine and University of Barcelona, Barcelona Science Park, Josep Samitier 1–5, Barcelona 08028, Spain 3 Centro de Investigaciones Biologicas (Consejo Superior de Investigaciones Cientificas), and CIBERER-ISCIII, Ramiro de Maeztu 9, Madrid 28040, Spain 4 Centro de Investigación Principe Felipe, and CIBERER-ISCIII, Avda. Autopista del Saler 16, Valencia 46013, Spain and 5 Servicio Neurologia, Fundación Jimenez Diaz, and CIBERER-ISCIII, Avda. Reyes Católicos 2, Madrid 28040, Spain
* To whom correspondence should be addressed. Tel: +3496 3391779; Fax: +3496 3690800; Email: sanz{at}ibv.csic.es
Received July 30, 2007; Accepted November 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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