The Lafora disease (LD, MIM 254780) is a fatal neurodegenerative disorder and the most frequent cause of progressive myoclonus epilepsy in Southern Europe. Most patients die within 10 years from the onset, following a rapid progression to a vegetative terminal state. LD is characterized by the presence of polyglucosan intracelular inclusion bodies (so-called Lafora bodies) showing a composition that resembles that of glycogen or amylopeptin. LD is inherited as an autosomal recessive trait. Two genes causing LD have been identified. EPM2A (6q24) encodes laforin, a dual protein tyrosine phosphatase. EPM2B (6p22.3) encodes malin, a putative E3-ubiquiting ligase. Patients carrying mutations in laforin are indistinguishable from those with mutations in malin. Using yeast two-hybrid analysis, immunoprecipitation and co-localization techniques, we have obtained evidence that laforin interacts with malin and with other proteins that participate in the assembly of the multiprotein complexes associated to the intracellular glycogen particles. These data reinforced the concept that laforin and malin are involved in the regulation of the glycogen metabolism. In collaboration with Joan Guinovart’s group at the IRB in Barcelona and with Pascual Sanz’s laboratory at the IBV-CSIC in Valencia, we have recently shown that the complex formed by laforin and malin regulates glycogen metabolism by a novel mechanism involving the ubiquitinilation and proteosomal degradation of GS and PTG proteins.These data explain the formation of Lafora bodies in neurons. Furthermore, we have established that the formation of the laforin-malin complex is controled by the AMPK protein. Our current goals are to define new laforin-malin targets and explain their contribution to LD. To this end we are developing several genetics, biochemical and cellular and molecular biology strategies. We expect that our results will increase our understanding of the molecular processes underlying the pathology and that this knowledge will allow us to delineate therapeutic approaches.