PRJNA434380
TDP-43 C-terminal mutations lead to a gain of function producing novel splicing events
TDP-43 (encoded by TARDBP) is an RNA binding protein with numerous functions in mRNA splicing. TDP-43 is central in the pathogenesis of neurodegenerative disorders including amyotrophic lateral sclerosis and frontotemporal dementia. In these diseases TDP-43 is depleted from nuclei but accumulates in cytoplasmic aggregates, suggesting loss-of-function plays a role in end-stage disease. However, its role in early-stage disease and how disease-causing TARDBP mutations trigger the pathogenic cascade remains unknown. Here we use three novel mice mutants carrying point mutations in endogenous Tardbp to dissect loss- and gain-of-TDP-43 function at physiological expression levels in vivo. We show TDP-43 C-terminal domain mutations lose autoregulation and causes a gain-of-function leading to neurodegenerative changes. Intriguingly, this gain-of-function induces novel splicing events, including skipping of constitutive exons, causing transcript dysregulation. These 'skiptic exons' occur in transcripts distinct from where previously described cryptic exons are found, highlighting how gain- and loss-of TDP-43 function affect RNA processing giving rise to distinct molecular signatures.