TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes
Yi Zeng, Anastasiia Lovchykova, Tetsuya Akiyama, Stephanie L. Rayner, Vidhya Bharathi, Chang Liu, Odilia Sianto, Caiwei Guo, Anna Calliari, Mercedes Prudencio, Dennis W. Dickson, Leonard Petrucelli, Aaron D. Gitler
Abstract
In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from the nucleus of neurons in the brain and spinal cord. A key function of TDP-43 has emerged as a repressor of cryptic exon inclusion during pre-mRNA splicing, but a role for TDP-43 in other RNA-processing events remains unresolved. Here we show that loss of TDP-43 from neuronal nuclei of human brain and disease-causing mutations in TDP-43 are associated with widespread changes in alternative polyadenylation (APA). Using high-resolution polyadenylation site mapping, we comprehensively defined TDP-43-regulated APA events in human stem cell-derived neurons and found that both the strength and position of TDP-43 binding influence polyA site usage. APA events caused by loss of TDP-43 impact expression of disease-relevant genes (for example, SFPQ, NEFL and TMEM106B). These findings provide evidence that, in addition to cryptic exon inclusion, APA changes are a new facet of TDP-43 pathology. Zeng et al. show that TDP-43, known for repressing cryptic exon usage in frontotemporal dementia/amyotrophic lateral sclerosis, also controls alternative polyadenylation, impacting expression of disease-linked genes (SFPQ, NEFL and TMEM106B).