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Acta Neuropathologica
Published in: Acta Neuropathologica 3/2011

01-09-2011 | Original Paper

Cell stress induces TDP-43 pathological changes associated with ERK1/2 dysfunction: implications in ALS

Authors: Victòria Ayala, Ana Belén Granado-Serrano, Daniel Cacabelos, Alba Naudí, Ekaterina V. Ilieva, Jordi Boada, Víctor Caraballo-Miralles, Jerònia Lladó, Isidro Ferrer, Reinald Pamplona, Manuel Portero-Otin

Published in: Acta Neuropathologica | Issue 3/2011

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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.
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Metadata
Title
Cell stress induces TDP-43 pathological changes associated with ERK1/2 dysfunction: implications in ALS
Authors
Victòria Ayala
Ana Belén Granado-Serrano
Daniel Cacabelos
Alba Naudí
Ekaterina V. Ilieva
Jordi Boada
Víctor Caraballo-Miralles
Jerònia Lladó
Isidro Ferrer
Reinald Pamplona
Manuel Portero-Otin
Publication date
01-09-2011
Publisher
Springer-Verlag
Published in
Acta Neuropathologica / Issue 3/2011
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-011-0850-y

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