TDP-43 aggregation is the pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-TDP). To define pathways important in TDP-43 proteinopathy, a genetic screen for modifiers of TDP-43-mediated eye degeneration was conducted in the fruit fly (Drosophila melanogaster). This approach and the following studies in the fly identified transcriptional elongation factor Ell as a potent dose-dependent modifier. Ell is a shared component of little elongation complex (LEC) and super elongation complex (SEC). Our studies show that downregulation of additional components in LEC or SEC partially but consistently ameliorates TDP-43-associated eye degeneration, implicating both Ell-associated complexes in TDP-43 toxicity. LEC regulates transcription of RNA Polymerase II (Pol II)-transcribed small nuclear RNAs (snRNAs), while SEC mainly regulates transcription of select inducible genes harboring paused Pol II including stress-induced loci. We hypothesized that, in the disease state, TDP-43 increases the activity of LEC and SEC, leading to enhanced expression of select target genes that contribute to neurodegeneration. Our results support this hypothesis by showing that select targets of LEC and SEC become upregulated in fly heads expressing TDP-43 compared to controls. Among upregulated targets, U12 snRNA and a stress-induced long non-coding RNA (lncRNA) Hsr were shown to functionally contribute to TDP-43-induced degeneration in Drosophila. The increase in U12 snRNA leads to elevated activity of the U12-dependent spliceosome, assessed by examining U12-dependent splicing events. Among the known U12 targets, the splicing of genes CG15735, CG16941 and CG11839 were shown to be upregulated selectively by TDP-43. In addition, the novel target of TDP-43 Hsr was identified by polytene chromosome association of TDP-43 and SEC components Lilli and Ell in the fly. We extended the findings of Hsr to show that the human orthologue Satellite III repeat (Sat III) is elevated in both a human cellular disease model of TDP-43 toxicity, and FTLD-TDP patient tissue. Furthermore, TDP-43 was shown to interact with human ELL2 by co-immunoprecipitation from human HEK293 cells. These findings support a model whereby TDP-43 promotes the LEC and SEC activities through an interaction with ELL2, leading to abnormal activation of LEC and SEC target genes that contribute to degeneration. These studies reveal the critical roles of Ell and Ell-associated complexes in TDP-43 toxicity, identify important downstream targets, and provide potential therapeutic strategies to combat TDP-43-associated neurodegeneration.