title: Increased oxidative stress and impaired antioxidant response in Lafora disease.
abstract: Lafora Disease (LD, OMIM 254780, ORPHA501) is a fatal neurodegenerative disorder characterized by the presence of glycogen-like intracellular inclusions called Lafora bodies and caused, in the vast majority of cases, by mutations in either EPM2A or EPM2B genes, encoding respectively laforin and malin. In the last years, several reports have revealed molecular details of these two proteins and have identified several processes affected in LD, but the pathophysiology of the disease still remains largely unknown. Since autophagy impairment has been reported as a characteristic treat in both Lafora disease cell and animal models, and as there is a link between autophagy and mitochondrial performance, we sought to determine if mitochondrial function could be altered in those models. Using fibroblasts from LD patients, deficient in laforin or malin, we found mitochondrial alterations, oxidative stress and a deficiency in antioxidant enzymes involved in the detoxification of reactive oxygen species (ROS). Similar results were obtained in brain tissue samples from transgenic mice deficient in either the EPM2A or EPM2B genes. Furthermore, in a proteomic analysis of brain tissue obtained from Epm2b-/- mice, we observed an increase in a modified form of peroxirredoxin-6, an antioxidant enzyme involved in other neurological pathologies, thus corroborating an alteration of the redox condition. These data support that oxidative stress produced by an increase in ROS production and an impairment of the antioxidant enzyme response to this stress play an important role in development of LD.
authors.affiliation: University of Valencia (Faculty of Medicine and Dentistry), Department of Physiology, Valencia, Spain. Electronic address: Carlos.Roma@uv.es.
authors.forename: Carlos
authors.initials: C
authors.lastname: Romá-Mateo
authors.affiliation: Centro de Investigación Príncipe Felipe (Intracellular Protein Degradation And Rare Diseases Laboratory), Valencia, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Aguado
authors.affiliation: University of Valencia (Faculty of Medicine and Dentistry), Department of Physiology, Valencia, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: García-Giménez
authors.affiliation: University of Valencia (Faculty of Medicine and Dentistry), Department of Physiology, Valencia, Spain.
authors.forename: José Santiago
authors.initials: JS
authors.lastname: Ibáñez-Cabellos
authors.affiliation: University of Valencia (Faculty of Medicine and Dentistry), Department of Physiology, Valencia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Seco-Cervera
authors.affiliation: University of Valencia (Faculty of Medicine and Dentistry), Department of Physiology, Valencia, Spain.
authors.forename: Federico V
authors.initials: FV
authors.lastname: Pallardó
authors.affiliation: Centro de Investigación Príncipe Felipe (Intracellular Protein Degradation And Rare Diseases Laboratory), Valencia, Spain.
authors.forename: Erwin
authors.initials: E
authors.lastname: Knecht
authors.affiliation: Instituto de Biomedicina de Valencia (CSIC), Laboratory of Nutrient Signalling, Valencia, Spain.
authors.forename: Pascual
authors.initials: P
authors.lastname: Sanz