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TDP-1/TDP-43 Regulates Stress Signaling and Age-Dependent Proteotoxicity in Caenorhabditis elegans

TDP-43 is a multifunctional nucleic acid binding protein linked to several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia. To learn more about the normal biological and abnormal pathological role of this protein, we turned to Caenorhabditis elega...

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Autores principales: Vaccaro, Alexandra, Tauffenberger, Arnaud, Ash, Peter E. A., Carlomagno, Yari, Petrucelli, Leonard, Parker, J. Alex
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390363/
https://www.ncbi.nlm.nih.gov/pubmed/22792076
http://dx.doi.org/10.1371/journal.pgen.1002806
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author Vaccaro, Alexandra
Tauffenberger, Arnaud
Ash, Peter E. A.
Carlomagno, Yari
Petrucelli, Leonard
Parker, J. Alex
author_facet Vaccaro, Alexandra
Tauffenberger, Arnaud
Ash, Peter E. A.
Carlomagno, Yari
Petrucelli, Leonard
Parker, J. Alex
author_sort Vaccaro, Alexandra
collection PubMed
description TDP-43 is a multifunctional nucleic acid binding protein linked to several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia. To learn more about the normal biological and abnormal pathological role of this protein, we turned to Caenorhabditis elegans and its orthologue TDP-1. We report that TDP-1 functions in the Insulin/IGF pathway to regulate longevity and the oxidative stress response downstream from the forkhead transcription factor DAF-16/FOXO3a. However, although tdp-1 mutants are stress-sensitive, chronic upregulation of tdp-1 expression is toxic and decreases lifespan. ALS–associated mutations in TDP-43 or the related RNA binding protein FUS activate the unfolded protein response and generate oxidative stress leading to the daf-16–dependent upregulation of tdp-1 expression with negative effects on neuronal function and lifespan. Consistently, deletion of endogenous tdp-1 rescues mutant TDP-43 and FUS proteotoxicity in C. elegans. These results suggest that chronic induction of wild-type TDP-1/TDP-43 by cellular stress may propagate neurodegeneration and decrease lifespan.
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spelling pubmed-33903632012-07-12 TDP-1/TDP-43 Regulates Stress Signaling and Age-Dependent Proteotoxicity in Caenorhabditis elegans Vaccaro, Alexandra Tauffenberger, Arnaud Ash, Peter E. A. Carlomagno, Yari Petrucelli, Leonard Parker, J. Alex PLoS Genet Research Article TDP-43 is a multifunctional nucleic acid binding protein linked to several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia. To learn more about the normal biological and abnormal pathological role of this protein, we turned to Caenorhabditis elegans and its orthologue TDP-1. We report that TDP-1 functions in the Insulin/IGF pathway to regulate longevity and the oxidative stress response downstream from the forkhead transcription factor DAF-16/FOXO3a. However, although tdp-1 mutants are stress-sensitive, chronic upregulation of tdp-1 expression is toxic and decreases lifespan. ALS–associated mutations in TDP-43 or the related RNA binding protein FUS activate the unfolded protein response and generate oxidative stress leading to the daf-16–dependent upregulation of tdp-1 expression with negative effects on neuronal function and lifespan. Consistently, deletion of endogenous tdp-1 rescues mutant TDP-43 and FUS proteotoxicity in C. elegans. These results suggest that chronic induction of wild-type TDP-1/TDP-43 by cellular stress may propagate neurodegeneration and decrease lifespan. Public Library of Science 2012-07-05 /pmc/articles/PMC3390363/ /pubmed/22792076 http://dx.doi.org/10.1371/journal.pgen.1002806 Text en Vaccaro et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Vaccaro, Alexandra
Tauffenberger, Arnaud
Ash, Peter E. A.
Carlomagno, Yari
Petrucelli, Leonard
Parker, J. Alex
TDP-1/TDP-43 Regulates Stress Signaling and Age-Dependent Proteotoxicity in Caenorhabditis elegans
title TDP-1/TDP-43 Regulates Stress Signaling and Age-Dependent Proteotoxicity in Caenorhabditis elegans
title_full TDP-1/TDP-43 Regulates Stress Signaling and Age-Dependent Proteotoxicity in Caenorhabditis elegans
title_fullStr TDP-1/TDP-43 Regulates Stress Signaling and Age-Dependent Proteotoxicity in Caenorhabditis elegans
title_full_unstemmed TDP-1/TDP-43 Regulates Stress Signaling and Age-Dependent Proteotoxicity in Caenorhabditis elegans
title_short TDP-1/TDP-43 Regulates Stress Signaling and Age-Dependent Proteotoxicity in Caenorhabditis elegans
title_sort tdp-1/tdp-43 regulates stress signaling and age-dependent proteotoxicity in caenorhabditis elegans
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390363/
https://www.ncbi.nlm.nih.gov/pubmed/22792076
http://dx.doi.org/10.1371/journal.pgen.1002806
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