TDP-1/TDP-43 regulates stress signaling and age-dependent proteotoxicity in Caenorhabditis elegans.

Authors: Vaccaro A; Tauffenberger A; Ash PE; Carlomagno Y; Petrucelli L; Parker JA

Abstract: 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.

Keywords: Amyotrophic Lateral Sclerosis/genetics/metabolism; Animals; Animals, Genetically Modified; Caenorhabditis elegans/*genetics/physiology; Caenorhabditis elegans Proteins/genetics/metabolism; DNA-Binding Proteins/*genetics/metabolism; Frontotemporal Dementia/genetics/metabolism; Gene Expression Regulation; Heat-Shock Proteins/metabolism; Humans; Insulin/genetics/metabolism; Longevity/*genetics/physiology; *Neurons/metabolism/pathology; *Oxidative Stress/genetics; Signal Transduction; Somatomedins/genetics/metabolism; Transcription Factors/genetics/metabolism
Journal: PLoS genetics
Volume: 8
Issue: 7
Pages: e1002806
Date: July 14, 2012
PMID: 22792076
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Vaccaro A, Tauffenberger A, Ash PE, Carlomagno Y, Petrucelli L, Parker JA (2012) TDP-1/TDP-43 regulates stress signaling and age-dependent proteotoxicity in Caenorhabditis elegans. PLoS genetics 8: e1002806.

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