Lafora progressive myoclonus epilepsy (Lafora disease) is a fatal autosomal recessive neurodegenerative disorder characterized by the presence of glycogen-like intracellular inclusions called Lafora bodies. The vast majority of patients carry mutations in either the EPM2A or EPM2B genes, encoding laforin, a glucan phosphatase, and malin, an E3 ubiquitin ligase, respectively.Although the precise physiological role of these proteins is not fully understood, work in past years has established a link between glycogen synthesis, Lafora bodies formation and Lafora disease development. To determine the role of the phosphatase activity of laforin in disease development we generated two Epm2a / mouse lines expressing either wild-type laforin or a mutant (C265S) laforin lacking only the phosphatase activity. Our results demonstrate that expression of either transgene blocks formation of Lafora bodies and restores the impairment in macroautophagy, preventing the development of Lafora bodies in Epm2a / mice. These data indicate that the critical pathogenic process is the control of abnormal glycogen accumulation through intracellular proteolytic systems by the laforin–malin complex, and not glycogen dephosphorylation by laforin.Understanding which is the essential process leading to Lafora disease pathogenesis represents a critical conceptual advance that should facilitate development of appropriate therapeutics. ; 45 p.-1 tab.-9 fig. ; J.G. holds a postdoctoral fellowship from the Program “Junta para la Ampliación de Estudios” (JAE-Doc) co-funded by the Fondo Social Europeo (FSE) and L.D-T. enjoys a FPU fellowship (AP2009-2698). This work was funded by the Spanish Ministerio de Economía y Competitividad (SAF2011-26583,BFU2011-22630 and BFU2010-16031), the Fundación Marato TV3 (Ref. 100132),the Consejo Superior de Investigaciones Cientificas (PIE 201020E043) and the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER).