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

• DOI: 10.1038/s41467-018-06543-0
• Publication Date: 2018-10-17T12:50:45Z
• Authors: 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
• Keywords: Male; 0301 basic medicine; RNA, Untranslated; Transcription Elongation, Genetic; Science; Q; Nuclear Proteins; Models, Biological; Article; DNA-Binding Proteins; 03 medical and health sciences; Drosophila melanogaster; HEK293 Cells; Genetic Loci; RNA, Small Nuclear; Animals; Drosophila Proteins; Humans; Female; Transcriptional Elongation Factors; Polytene Chromosomes; Protein Binding; Transcription Factors

AbstractTDP-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.