title: The phosphatase activity of laforin is dispensable to rescue Epm2a-/- mice from Lafora disease.
abstract: 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.
authors.affiliation: 1 Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones, Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Gayarre
authors.forename: Lara
authors.initials: L
authors.lastname: Duran-Trío
authors.forename: Olga
authors.initials: O
authors.lastname: Criado Garcia
authors.forename: Carmen
authors.initials: C
authors.lastname: Aguado
authors.forename: Lucia
authors.initials: L
authors.lastname: Juana-López
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Crespo
authors.forename: Erwin
authors.initials: E
authors.lastname: Knecht
authors.forename: Paola
authors.initials: P
authors.lastname: Bovolenta
authors.forename: Santiago
authors.initials: S
authors.lastname: Rodríguez de Córdoba
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D004195:Disease Models, Animal; D054637:Dual-Specificity Phosphatases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020192:Lafora Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D010766:Phosphorylation / Q000235:genetics; D054558:Protein Tyrosine Phosphatases, Non-Receptor
chemical_list: D054637:Dual-Specificity Phosphatases; C491989:Epm2a protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor
keywords: Lafora bodies; Lafora disease; autophagy; glycogen phosphorylation; phosphatase activity