TAR 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 since 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.

TDP-43 is recruited to stress granules in conditions of oxidative insult / C. Colombrita, E. Zennaro, C. Fallini, M. Weber, A. Sommacal, E. Buratti, V. Silani, A. Ratti. - In: JOURNAL OF NEUROCHEMISTRY. - ISSN 0022-3042. - 111:4(2009), pp. 1051-1061.

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

V. Silani
Penultimo
;
A. Ratti
Ultimo
2009

Abstract

TAR 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 since 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.
Amyotrophic lateral sclerosis; RNA-binding protein; Stress granules; Transactive response DNA-binding protein 43
Settore MED/26 - Neurologia
Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica
   Alterations of Axonal Functions and Neurodegeneration in Motor Neuron Diseases
   FONDAZIONE CARIPLO
   2008.2307
2009
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/70353
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