An ALS-associated TARDBP mutation drives cryptic exon inclusion and RNA dysregulation

TAR DNA binding protein 43 (TDP-43) proteinopathy is a defining pathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet the downstream molecular events linking TDP-43 dysfunction to neurodegeneration remain incompletely understood. Here, we model TDP-43 proteinopathy by introducing the ALS/FTD associated TARDBP K181E mutation into human induced pluripotent stem cells and differentiating them into three-dimensional forebrain organoids. Organoids carrying the K181E mutation exhibit spontaneous TDP-43 hyperphosphorylation, cytoplasmic p-TDP43 accumulation, RNA dysregulation, pro-inflammatory signaling, and activation of apoptotic pathways without TDP-4