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

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.

Functional Roles of Long Non-coding RNAs in Motor Neuron Development and Disease

“…Mechanistically, hsrω interacts with dFUS, and depletion of hsrω results in dFUS translocation into the cytoplasm and abrogation of its nuclear function [79]. Levels of hsrω are positively regulated by TDP-43 via direct binding of TDP-43 to the hsrω locus in Drosophila [29]. The human orthologue of Drosophila hsrω, stress-induced Satellite III repeat RNA (Sat III), has also been shown to be elevated upon TDP-43 overexpression in the frontal cortex of FTLD-TDP patients [29].…”

Conservation of gene architecture and domains amidst sequence divergence in thehsrωlncRNA gene across theDrosophilagenus: Anin silicoanalysis

“…Together, it seems very likely that a functional equivalent of Drosophila orthologue is present in diverse dipterans as well, specific identification of which would need multi-pronged comprehensive cytogenetic, cell biological and genomic approaches. Functional similarity between the cell stress-inducible Sat III repetitive transcripts in human cells and the hsrω transcripts (Chung, et al, 2018;Jolly and Lakhotia, 2006) suggests that gene loci producing lncRNAs functionally analogous to hsrω transcripts indeed exist in diverse taxa as well.…”

“…Apparently, the tandem repeats of the hsrω gene discharge their common functions despite the sequence variations. Interestingly, the Human repetitive Sat III sequences, functional equivalents of the hsrω gene (Chung, et al, 2018;Jolly and Lakhotia, 2006), do not show any similarity with tandem repeats of the hsrω gene but still perform comparable functions. As known for many lncRNAs, especially for those associated with membraneless phase-separated nuclear sub-structures, the secondary and higher order structures attained by the specific lncRNA orthologue are critical Lin, et al, 2018).…”

Functional roles and networks of non-coding RNAs in the pathogenesis of neurodegenerative diseases

“…Using tissues from postmortem ALS/ FTLD patients, TDP43 was associated with upregulation of the snRNA U12 and the ncRNA Hsrw (stressinduced satellite III repeat RNA), both of which are linked to neurodegeneration in ALS/FTLD. Mechanistically, upregulation of U12 snRNA and Hsrw is caused by an interaction between TDP43 and transcription elongation factor ELL2, a shared component of the little elongation complex and super elongation complex [131]. Using iCLIP in FTLS-TDP/ALS postmortem tissues, it was also shown that NEAT1 interacts with TDP43 and FUS/TLS [132,133].…”