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., Chen-Plotkin, A., Bonini, N.M. (2018). Aberrant activation of non-coding RNA targets of transcriptional elongation complexes contributes to TDP-43 toxicity.  Nat. Commun. 9(1): 4406.

FBrf0241072

Research paper

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.

PMC6199344 (PMC) (EuropePMC)