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 and Nancy M. Bonini ()
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Chia-Yu Chung: University of Pennsylvania
Amit Berson: University of Pennsylvania
Jason R. Kennerdell: University of Pennsylvania
Ashley Sartoris: University of Pennsylvania
Travis Unger: Perelman School of Medicine
Sílvia Porta: Perelman School of Medicine
Hyung-Jun Kim: University of Pennsylvania
Edwin R. Smith: Northwestern University
Ali Shilatifard: Northwestern University
Vivianna Van Deerlin: Perelman School of Medicine
Virginia M.-Y. Lee: Perelman School of Medicine
Alice Chen-Plotkin: Perelman School of Medicine
Nancy M. Bonini: University of Pennsylvania

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06543-0

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DOI: 10.1038/s41467-018-06543-0

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