TDP-1, the Caenorhabditis elegans ortholog of TDP-43, limits the accumulation of double-stranded RNA

Tassa K. Saldi, Peter E.A. Ash, Gavin Wilson, Patrick Gonzales, Alfonso Garrido-Lecca, Christine M. Roberts, Vishantie Dostal, Tania F. Gendron, Lincoln D. Stein, Thomas Blumenthal, Leonard Petrucelli, Christopher D. Link

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Caenorhabditis elegans mutants deleted for TDP-1, an ortholog of the neurodegeneration-associated RNA-binding protein TDP-43, display only mild phenotypes. Nevertheless, transcriptome sequencing revealed that many RNAs were altered in accumulation and/or processing in the mutant. Analysis of these transcriptional abnormalities demonstrates that a primary function of TDP-1 is to limit formation or stability of double-stranded RNA. Specifically, we found that deletion of tdp-1: (1) preferentially alters the accumulation of RNAs with inherent double-stranded structure (dsRNA); (2) increases the accumulation of nuclear dsRNA foci; (3) enhances the frequency of adenosine-to-inosine RNA editing; and (4) dramatically increases the amount of transcripts immunoprecipitable with a dsRNA-specific antibody, including intronic sequences, RNAs with antisense overlap to another transcript, and transposons. We also show that TDP-43 knockdown in human cells results in accumulation of dsRNA, indicating that suppression of dsRNA is a conserved function of TDP-43 in mammals. Altered accumulation of structured RNA may account for some of the previously described molecular phenotypes (e.g., altered splicing) resulting from reduction of TDP-43 function. Synopsis Mutations in RNA-binding protein TDP-43 are linked to ALS. This study reports that the worm homolog of TDP-43, TDP-1, limits the accumulation of double-stranded RNAs, offering insight on the potential contribution of TDP-43/TDP-1 to disease onset. TDP-1 acts co-transcriptionally to limit the accumulation of dsRNA TDP-1 limits A-to-I RNA editing TDP-1 maintains chemotaxis by limiting the action of RNA interference Knockdown of TDP-43 in human cells leads to an increase in dsRNA, potentially inducing an interferon response Human TDP-43 can act as an RNA chaperone in vitro Mutations in RNA-binding protein TDP-43 are linked to ALS. This study reports that the worm homolog of TDP-43, TDP-1, limits the accumulation of double-stranded RNAs, offering insight on the potential contribution of TDP-43/TDP-1 to disease onset.

Original languageEnglish (US)
Pages (from-to)2947-2966
Number of pages20
JournalEMBO Journal
Volume33
Issue number24
DOIs
StatePublished - Dec 17 2014

Keywords

  • RNA editing
  • RNA structure
  • neurodegeneration
  • splicing

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Saldi, T. K., Ash, P. E. A., Wilson, G., Gonzales, P., Garrido-Lecca, A., Roberts, C. M., Dostal, V., Gendron, T. F., Stein, L. D., Blumenthal, T., Petrucelli, L., & Link, C. D. (2014). TDP-1, the Caenorhabditis elegans ortholog of TDP-43, limits the accumulation of double-stranded RNA. EMBO Journal, 33(24), 2947-2966. https://doi.org/10.15252/embj.201488740