TDP-43 is recruited to stress granules in conditions of oxidative insult

Claudia Colombrita, Eleonora Zennaro, Claudia Fallini, Markus Weber, Andreas Sommacal, Emanuele Buratti, Vincenzo Silani, Antonia Ratti

Research output: Contribution to journalArticle

Abstract

Transactive response DNA-binding protein 43 (TDP-43) forms abnormal ubiquitinated and phosphorylated inclusions in brain tissues from patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. TDP-43 is a DNA/RNA-binding protein involved in RNA processing, such as transcription, pre-mRNA splicing, mRNA stabilization and transport to dendrites. We found that in response to oxidative stress and to environmental insults of different types TDP-43 is capable to assemble into stress granules (SGs), ribonucleoprotein complexes where protein synthesis is temporarily arrested. We demonstrated that a specific aminoacidic interval (216-315) in the C-terminal region and the RNA-recognition motif 1 domain are both implicated in TDP-43 participation in SGs as their deletion prevented the recruitment of TDP-43 into SGs. Our data show that TDP-43 is a specific component of SGs and not of processing bodies, although we proved that TDP-43 is not necessary for SG formation, and its gene silencing does not impair cell survival during stress. The analysis of spinal cord tissue from ALS patients showed that SG markers are not entrapped in TDP-43 pathological inclusions. Although SGs were not evident in ALS brains, we speculate that an altered control of mRNA translation in stressful conditions may trigger motor neuron degeneration at early stages of the disease.

Original languageEnglish
Pages (from-to)1051-1061
Number of pages11
JournalJournal of Neurochemistry
Volume111
Issue number4
DOIs
Publication statusPublished - Nov 2009

Keywords

  • Amyotrophic lateral sclerosis
  • RNA-binding protein
  • Stress granules
  • Transactive response DNA-binding protein 43

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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