4.6 Article

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

Journal

ACTA NEUROPATHOLOGICA
Volume 122, Issue 3, Pages 259-270

Publisher

SPRINGER
DOI: 10.1007/s00401-011-0850-y

Keywords

Oxidative stress; Proteasome stress; Endoplasmic reticulum stress; Excitotoxicity; ALS; TDP-43; ERK1/2

Funding

  1. Spanish Ministry of Education and Science [BFU 2009-11879/BFI, AGL2006-12433, BFU 2009-06427/E]
  2. Generalitat of Catalunya [2009SGR-735]
  3. Spanish Ministry of Health [PI08-1843, BESAD-P, PI08-0582]
  4. ALS Catalan Foundation
  5. La Caixa Foundation
  6. COST [B-35]
  7. Govern Balear, Conselleria d' Economia Hisenda i Innovacio
  8. Instituto de Salud Carlos III

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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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