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

TLDR

TDP‑43 is a DNA/RNA‑binding protein that forms abnormal ubiquitinated and phosphorylated inclusions in ALS and frontotemporal lobar degeneration and normally regulates RNA processing. The study aimed to determine whether TDP‑43’s recruitment to stress granules under oxidative insult could contribute to early motor neuron degeneration in ALS. TDP‑43 is recruited to stress granules during oxidative stress via its C‑terminal 216–315 region and RRM1 domain, but its presence is not required for SG assembly or cell survival, and SG markers are absent from TDP‑43 inclusions in ALS spinal cord.

Abstract

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.