title: Cell stress induces TDP-43 pathological changes associated with ERK1/2 dysfunction: implications in ALS.
abstract: TDP-43 has been implicated in the pathogenesis of amyotrophic lateral sclerosis and other neurodegenerative diseases. Here we demonstrate, using neuronal and spinal cord organotypic culture models, that chronic excitotoxicity, oxidative stress, proteasome dysfunction and endoplasmic reticulum stress mechanistically induce mislocalization, phosphorylation and aggregation of TDP-43. This is compatible with a lack of function of this protein in the nucleus, specially in motor neurons. The relationship between cell stress and pathological changes of TDP-43 also includes a dysfunction in the survival pathway mediated by mitogen-activated protein kinase/extracellular signal-regulated kinases (ERK1/2). Thus, under stress conditions, neurons and other spinal cord cells showed cytosolic aggregates containing ERK1/2. Moreover, aggregates of abnormal phosphorylated ERK1/2 were also found in the spinal cord in amyotrophic lateral sclerosis (ALS), specifically in motor neurons with abnormal immunoreactive aggregates of phosphorylated TDP-43. These results demonstrate that cellular stressors are key factors in neurodegeneration associated with TDP-43 and disclose the identity of ERK1/2 as novel players in the pathogenesis of ALS.
authors.affiliation: Grup de Fisiopatologia Metabòlica, Departament de Medicina Experimental, Universitat de Lleida-IRBLleida, Lleida, Spain.
authors.forename: Victòria
authors.initials: V
authors.lastname: Ayala
authors.forename: Ana Belén
authors.initials: AB
authors.lastname: Granado-Serrano
authors.forename: Daniel
authors.initials: D
authors.lastname: Cacabelos
authors.forename: Alba
authors.initials: A
authors.lastname: Naudí
authors.forename: Ekaterina V
authors.initials: EV
authors.lastname: Ilieva
authors.forename: Jordi
authors.initials: J
authors.lastname: Boada
authors.forename: Víctor
authors.initials: V
authors.lastname: Caraballo-Miralles
authors.forename: Jerònia
authors.initials: J
authors.lastname: Lladó
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
authors.forename: Reinald
authors.initials: R
authors.lastname: Pamplona
authors.forename: Manuel
authors.initials: M
authors.lastname: Portero-Otin
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D000818:Animals; D000831:Animals, Newborn; D016022:Case-Control Studies; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009046:Motor Neurons / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology; D009924:Organ Culture Techniques; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology*; D019284:Thapsigargin / Q000494:pharmacology; D014162:Transfection / Q000379:methods
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D016877:Oxidants; D019284:Thapsigargin; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases; C078846:epoxomicin