TDP-43 is recruited to stress granules in conditions of oxidative insult.
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.
Colombrita
Claudia
C
Department of Neurology and Laboratory of Neuroscience, Dino Ferrari Center, Università degli Studi di Milano - IRCCS Istituto Auxologico Italiano, Milan, Italy.
Zennaro
Eleonora
E
Fallini
Claudia
C
Weber
Markus
M
Sommacal
Andreas
A
Buratti
Emanuele
E
Silani
Vincenzo
V
Ratti
Antonia
A
D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D018053:Arsenites / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D004640:Emetine / Q000494:pharmacology; D006358:Hot Temperature / Q000009:adverse effects; D006822:Hybrid Cells; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013723:Teratogens / Q000494:pharmacology*; D014162:Transfection / Q000379:methods
D000954:Antigens, Surface; D018053:Arsenites; D004268:DNA-Binding Proteins; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D011500:Protein Synthesis Inhibitors; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; D013723:Teratogens; C015001:arsenite; D004640:Emetine