TDP-43 nuclear loss in FTD-ALS causes widespread alternative polyadenylation

In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from the nucleus. TDP-43 loss leads to cryptic exon inclusion but a role in other RNA processing events remains unresolved. Here, we show that loss of TDP-43 causes widespread changes in alternative polyadenylation, impacting expression of disease-relevant genes (e.g., ELP1, NEFL, and TMEM106B), providing evidence that alternative polyadenylation is a new facet to TDP-43 pathology. Overall design: To investigate the role of TDP-43 regulated alternative polyadenylation in FTD and ALS, we differentiated human stem cells to cortical neurons, used shRNA to knock down TDP-43, and then performed RNA-seq and 3' end-seq to examine the impact of TDP-43 knockdown on alternative polyadenylation and corresponding gene expression changes.