Neurotoxic effects of TDP-43 overexpression in C. elegans

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

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134 Scopus citations

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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ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Ash, P. E. A., Zhang, Y. J., Roberts, C. M., Saldi, T., Hutter, H., Buratti, E., Petrucelli, L., & 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