Aberrant activation of non-coding RNA targets of transcriptional elongation complexes contributes to TDP-43 toxicity

Chia Yu Chung, Amit Berson, Jason R. Kennerdell, Ashley Sartoris, Travis Unger, Sílvia Porta, Hyung Jun Kim, Edwin R. Smith, Ali Shilatifard, Vivianna Van Deerlin, Virginia M.Y. Lee, Alice Chen-Plotkin, Nancy M. Bonini*

*Corresponding author for this work

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10 Scopus citations

Abstract

TDP-43 is the major disease protein associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-TDP). Here we identify the transcriptional elongation factor Ell—a shared component of little elongation complex (LEC) and super elongation complex (SEC)—as a strong modifier of TDP-43-mediated neurodegeneration. Our data indicate select targets of LEC and SEC become upregulated in the fly ALS/FTLD-TDP model. Among them, U12 snRNA and a stress-induced long non-coding RNA Hsrω, functionally contribute to TDP-43-mediated degeneration. We extend the findings of Hsrω, which we identify as a chromosomal target of TDP-43, to show that the human orthologue Sat III is elevated in a human cellular disease model and FTLD-TDP patient tissue. We further demonstrate an interaction between TDP-43 and human ELL2 by co-immunoprecipitation from human cells. These findings reveal important roles of Ell-complexes LEC and SEC in TDP-43-associated toxicity, providing potential therapeutic insight for TDP-43-associated neurodegeneration.

Original languageEnglish (US)
Article number4406
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Chung, C. Y., Berson, A., Kennerdell, J. R., Sartoris, A., Unger, T., Porta, S., Kim, H. J., Smith, E. R., Shilatifard, A., Van Deerlin, V., Lee, V. M. Y., Chen-Plotkin, A., & Bonini, N. M. (2018). Aberrant activation of non-coding RNA targets of transcriptional elongation complexes contributes to TDP-43 toxicity. Nature communications, 9(1), [4406]. https://doi.org/10.1038/s41467-018-06543-0