TARDBP and proteostasis deficiencies: Our study establishes an iPSC-based forebrain brain organoid model carrying the ALS- and FTD-associated TDP-43 K181E mutation, which recapitulates key phenotypes of TDP-43 proteinopathies including endogenous TDP-43 cytoplasmic hyperphosphorylation, RNA dysregulation, disturbed protein homeostasis, neuroinflammation, and cell death.