title: Oxidative stress, a new hallmark in the pathophysiology of Lafora progressive myoclonus epilepsy.
abstract: Lafora disease (LD; OMIM 254780, ORPHA501) is a devastating neurodegenerative disorder characterized by the presence of glycogen-like intracellular inclusions called Lafora bodies and caused, in most cases, by mutations in either the EPM2A or the EPM2B gene, encoding respectively laforin, a phosphatase with dual specificity that is involved in the dephosphorylation of glycogen, and malin, an E3-ubiquitin ligase involved in the polyubiquitination of proteins related to glycogen metabolism. Thus, it has been reported that laforin and malin form a functional complex that acts as a key regulator of glycogen metabolism and that also plays a crucial role in protein homeostasis (proteostasis). Regarding this last function, it has been shown that cells are more sensitive to ER stress and show defects in proteasome and autophagy activities in the absence of a functional laforin-malin complex. More recently, we have demonstrated that oxidative stress accompanies these proteostasis defects and that various LD models show an increase in reactive oxygen species and oxidative stress products together with a dysregulated antioxidant enzyme expression and activity. In this review we discuss possible connections between the multiple defects in protein homeostasis present in LD and oxidative stress.
authors: Fundación Investigación Clinico de Valencia, Instituto de Investigación Sanitaria, Valencia, Spain; Department of Physiology, School of Medicine and Dentistry, University of Valencia, E46010 Valencia, Spain.
authors: Carlos
authors: C
authors: Romá-Mateo
authors: Centro de Investigación Biomédica en Red de Enfermedades Raras, Valencia, Spain; Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors: Carmen
authors: C
authors: Aguado
authors: Fundación Investigación Clinico de Valencia, Instituto de Investigación Sanitaria, Valencia, Spain; Department of Physiology, School of Medicine and Dentistry, University of Valencia, E46010 Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Valencia, Spain.
authors: José Luis
authors: JL
authors: García-Giménez
authors: Centro de Investigación Biomédica en Red de Enfermedades Raras, Valencia, Spain; Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors: Erwin
authors: E
authors: Knecht
authors: Centro de Investigación Biomédica en Red de Enfermedades Raras, Valencia, Spain; Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas, Valencia, Spain.
authors: Pascual
authors: P
authors: Sanz
authors: Fundación Investigación Clinico de Valencia, Instituto de Investigación Sanitaria, Valencia, Spain; Department of Physiology, School of Medicine and Dentistry, University of Valencia, E46010 Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Valencia, Spain. Electronic address: Federico.V.Pallardo@uv.es.
authors: Federico V
authors: FV
authors: Pallardó
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D006003:Glycogen / Q000378:metabolism; D006801:Humans; D020192:Lafora Disease / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation; D018384:Oxidative Stress; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics; D057165:Proteostasis Deficiencies / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
chemical_list: D000975:Antioxidants; D002352:Carrier Proteins; D006003:Glycogen; C478960:NHLRC1 protein, human; D044767:Ubiquitin-Protein Ligases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C114990:EPM2A protein, human
keywords: Free radicals; Lafora disease; Laforin; Malin; Oxidative stress; Proteostasis