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

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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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Acknowledgments

We are indebted to tissue donors and their families. This work was supported by grants from Spanish Ministry of Education and Science [grant numbers BFU 2009-11879/BFI, AGL2006-12433, BFU 2009-06427/E]; the Generalitat of Catalunya [grant number 2009SGR-735]; the Spanish Ministry of Health [grant number PI08-1843 to M.P.O., BESAD-P and PI08-0582 to I.F.]; the ALS Catalan Foundation [to I.F.]; and “La Caixa” Foundation. Supported also by the COST B-35 Action. V.C has been supported by a predoctoral fellowship from Govern Balear, Conselleria d’ Economia Hisenda i Innovació and D.C. by a predoctoral fellowship from the Instituto de Salud Carlos III.

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Authors and Affiliations

  1. Grup de Fisiopatologia Metabòlica, Departament de Medicina Experimental, Universitat de Lleida-IRBLleida, Lleida, Spain

    Victòria Ayala, Ana Belén Granado-Serrano, Daniel Cacabelos, Alba Naudí, Ekaterina V. Ilieva, Jordi Boada, Reinald Pamplona & Manuel Portero-Otin

  2. Departament de Biologia, IUNICS, Universitat de les Illes Balears, Palma de Mallorca, Spain

    Víctor Caraballo-Miralles & Jerònia Lladó

  3. Institut de Neuropatologia, Hospital Universitari de Bellvitge, IDIBELL, Universitat de Barcelona, L’Hospitalet de Llobregat, Spain

    Isidro Ferrer

  4. CIBERNED (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas), Instituto Carlos III, Spanish Ministry of Health, Madrid, Spain

    Isidro Ferrer

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  1. Victòria Ayala
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  2. Ana Belén Granado-Serrano
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Correspondence to Manuel Portero-Otin.

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V. Ayala and A. B. Granado-Serrano contributed equally to this work.

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Ayala, V., Granado-Serrano, A.B., Cacabelos, D. et al. Cell stress induces TDP-43 pathological changes associated with ERK1/2 dysfunction: implications in ALS. Acta Neuropathol 122, 259–270 (2011). https://doi.org/10.1007/s00401-011-0850-y

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  • DOI: https://doi.org/10.1007/s00401-011-0850-y

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