Neurotoxic effects of TDP-43 overexpression in C. elegans

Peter E A Ash, Yongjie Zhang, Christine M. Roberts, Tassa Saldi, Harald Hutter, Emanuele Buratti, Leonard Petrucelli, Christopher D. Link

Research output: Contribution to journalArticle

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Abstract

RNA-binding protein TDP-43 has been associated with multiple neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal lobar dementia. We have engineered pan-neuronal expression of human TDP-43 protein in Caenorhabditis elegans, with the goal of generating a convenient in vivo model of TDP-43 function and neurotoxicity. Transgenic worms with the neuronal expression of human TDP-43 exhibit an 'uncoordinated' phenotype and have abnormal motorneuron synapses. Caenorhabditis elegans contains a single putative ortholog of TDP-43, designated TDP-1, which we show can support alternative splicing of CFTR in a cell-based assay. Neuronal overexpression of TDP-1 also results in an uncoordinated phenotype, while genetic deletion of the tdp-1 gene does not affect movement or alter motorneuron synapses. By using the uncoordinated phenotype as a read-out of TDP-43 overexpression neurotoxicty, we have investigated the contribution of specific TDP-43 domains and subcellular localization to toxicity. Full-length (wild-type) human TDP-43 expressed in C. elegans is localized to the nucleus. Deletion of either RNA recognition domain (RRM1 or RRM2) completely blocks neurotoxicity, as does deletion of the C-terminal region. These deleted TDP-43 variants still accumulate in the nucleus, although their subnuclear distribution is altered. Interestingly, fusion of TDP-1 C-terminal sequences to TDP-43 missing its C-terminal domain restores normal subnuclear localization and toxicity in C. elegans and CFTR splicing in cell-based assays. Overexpression of wild-type, full-length TDP-43 in mammalian cells (differentiated M17 cells) can also result in cell toxicity. Our results demonstrate that in vivo TDP-43 neurotoxicity can result from nuclear activity of overexpressed full-length protein.

Original languageEnglish (US)
Article numberddq230
Pages (from-to)3206-3218
Number of pages13
JournalHuman Molecular Genetics
Volume19
Issue number16
DOIs
StatePublished - Jun 8 2010

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Caenorhabditis elegans
Phenotype
Synapses
RNA-Binding Proteins
Alternative Splicing
Neurodegenerative Diseases
RNA
Genes
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Ash, P. E. A., Zhang, Y., Roberts, C. M., Saldi, T., Hutter, H., Buratti, E., ... Link, C. D. (2010). Neurotoxic effects of TDP-43 overexpression in C. elegans. Human Molecular Genetics, 19(16), 3206-3218. [ddq230]. https://doi.org/10.1093/hmg/ddq230

Neurotoxic effects of TDP-43 overexpression in C. elegans. / Ash, Peter E A; Zhang, Yongjie; Roberts, Christine M.; Saldi, Tassa; Hutter, Harald; Buratti, Emanuele; Petrucelli, Leonard; Link, Christopher D.

In: Human Molecular Genetics, Vol. 19, No. 16, ddq230, 08.06.2010, p. 3206-3218.

Research output: Contribution to journalArticle

Ash, PEA, Zhang, Y, Roberts, CM, Saldi, T, Hutter, H, Buratti, E, Petrucelli, L & Link, CD 2010, 'Neurotoxic effects of TDP-43 overexpression in C. elegans', Human Molecular Genetics, vol. 19, no. 16, ddq230, pp. 3206-3218. https://doi.org/10.1093/hmg/ddq230
Ash PEA, Zhang Y, Roberts CM, Saldi T, Hutter H, Buratti E et al. Neurotoxic effects of TDP-43 overexpression in C. elegans. Human Molecular Genetics. 2010 Jun 8;19(16):3206-3218. ddq230. https://doi.org/10.1093/hmg/ddq230
Ash, Peter E A ; Zhang, Yongjie ; Roberts, Christine M. ; Saldi, Tassa ; Hutter, Harald ; Buratti, Emanuele ; Petrucelli, Leonard ; Link, Christopher D. / Neurotoxic effects of TDP-43 overexpression in C. elegans. In: Human Molecular Genetics. 2010 ; Vol. 19, No. 16. pp. 3206-3218.
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