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PMID:22792076

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Citation

Vaccaro, A, Tauffenberger, A, Ash, PE, Carlomagno, Y, Petrucelli, L and Parker, JA (2012) TDP-1/TDP-43 regulates stress signaling and age-dependent proteotoxicity in Caenorhabditis elegans. PLoS Genet. 8:e1002806

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.

Links

PubMed PMC3390363 Online version:10.1371/journal.pgen.1002806

Keywords

Amyotrophic Lateral Sclerosis/genetics; Amyotrophic Lateral Sclerosis/metabolism; Animals; Animals, Genetically Modified; Caenorhabditis elegans/genetics; Caenorhabditis elegans/physiology; Caenorhabditis elegans Proteins/genetics; Caenorhabditis elegans Proteins/metabolism; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Forkhead Transcription Factors; Frontotemporal Dementia/genetics; Frontotemporal Dementia/metabolism; Gene Expression Regulation; Heat-Shock Proteins/metabolism; Humans; Insulin/genetics; Insulin/metabolism; Longevity/genetics; Longevity/physiology; Neurons/metabolism; Neurons/pathology; Oxidative Stress/genetics; Signal Transduction; Somatomedins/genetics; Somatomedins/metabolism; Transcription Factors/genetics; Transcription Factors/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

CAEEL:TADBP

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CAEEL:TADBP

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000898

P

  • has_input:(WB:WBGene00004932)

Seeded From UniProt

complete

CAEEL:TADBP

involved_in

GO:0008340: determination of adult lifespan

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:TADBP

involved_in

GO:0006979: response to oxidative stress

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:TADBP

involved_in

GO:0006979: response to oxidative stress

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:TADBP

involved_in

GO:0006979: response to oxidative stress

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000898

P

Seeded From UniProt

complete

CAEEL:TADBP

involved_in

GO:0006972: hyperosmotic response

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:TADBP

involved_in

GO:0008340: determination of adult lifespan

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000898

P

Seeded From UniProt

complete

CAEEL:TADBP

involved_in

GO:0006972: hyperosmotic response

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:D0VWM8

involved_in

GO:0006979: response to oxidative stress

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000898

P

Seeded From UniProt

complete

CAEEL:D0VWM8

involved_in

GO:0008340: determination of adult lifespan

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:D0VWM8

involved_in

GO:0008340: determination of adult lifespan

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000898

P

Seeded From UniProt

complete

CAEEL:D0VWM8

involved_in

GO:0006979: response to oxidative stress

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:D0VWM8

involved_in

GO:0006972: hyperosmotic response

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:D0VWM8

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000898

P

has_regulation_target:(WB:WBGene00004932)

Seeded From UniProt

complete

CAEEL:D0VWM8

involved_in

GO:0006979: response to oxidative stress

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:D0VWM8

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CAEEL:D0VWM8

involved_in

GO:0006972: hyperosmotic response

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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