title: Lafora bodies and neurological defects in malin-deficient mice correlate with impaired autophagy.
abstract: Lafora disease (LD), a fatal neurodegenerative disorder characterized by the presence of intracellular inclusions called Lafora bodies (LBs), is caused by loss-of-function mutations in laforin or malin. Previous studies suggested a role of these proteins in the regulation of glycogen biosynthesis, in glycogen dephosphorylation and in the modulation of the intracellular proteolytic systems. However, the contribution of each of these processes to LD pathogenesis is unclear. We have generated a malin-deficient (Epm2b-/-) mouse with a phenotype similar to that of LD patients. By 3-6 months of age, Epm2b-/- mice present neurological and behavioral abnormalities that correlate with a massive presence of LBs in the cortex, hippocampus and cerebellum. Sixteen-day-old Epm2b-/- mice, without detectable LBs, show an impairment of macroautophagy (hereafter called autophagy), which remains compromised in adult animals. These data demonstrate similarities between the Epm2a-/- and Epm2b-/- mice that provide further insights into LD pathogenesis. They illustrate that the dysfunction of autophagy is a consequence of the lack of laforin-malin complexes and a common feature of both mouse models of LD. Because this dysfunction precedes other pathological manifestations, we propose that decreased autophagy plays a primary role in the formation of LBs and it is critical in LD pathogenesis.
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Criado
authors.forename: Carmen
authors.initials: C
authors.lastname: Aguado
authors.forename: Javier
authors.initials: J
authors.lastname: Gayarre
authors.forename: Lara
authors.initials: L
authors.lastname: Duran-Trio
authors.forename: Ana M
authors.initials: AM
authors.lastname: Garcia-Cabrero
authors.forename: Santiago
authors.initials: S
authors.lastname: Vernia
authors.forename: Beatriz
authors.initials: B
authors.lastname: San Millán
authors.forename: Miguel
authors.initials: M
authors.lastname: Heredia
authors.forename: Carlos
authors.initials: C
authors.lastname: Romá-Mateo
authors.forename: Silvana
authors.initials: S
authors.lastname: Mouron
authors.forename: Lucía
authors.initials: L
authors.lastname: Juana-López
authors.forename: Mercedes
authors.initials: M
authors.lastname: Domínguez
authors.forename: Carmen
authors.initials: C
authors.lastname: Navarro
authors.forename: Jose M
authors.initials: JM
authors.lastname: Serratosa
authors.forename: Marina
authors.initials: M
authors.lastname: Sanchez
authors.forename: Pascual
authors.initials: P
authors.lastname: Sanz
authors.forename: Paola
authors.initials: P
authors.lastname: Bovolenta
authors.forename: Erwin
authors.initials: E
authors.lastname: Knecht
authors.forename: Santiago
authors.initials: S
authors.lastname: Rodriguez de Cordoba
mesh_terms: D000818:Animals; D001343:Autophagy; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D054637:Dual-Specificity Phosphatases / Q000032:analysis / Q000378:metabolism; D005936:Glucans / Q000737:chemistry; D020192:Lafora Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D019957:Motor Skills Disorders / Q000235:genetics; D009206:Myocardium / Q000648:ultrastructure; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D025801:Ubiquitin / Q000032:analysis; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics*
chemical_list: D005936:Glucans; D025801:Ubiquitin; C083094:polyglucosan; C572596:NHLRC1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D054637:Dual-Specificity Phosphatases; C491989:Epm2a protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor