Project description:TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS). Here, we show that ALS subjects have reduced early-phase insulin secretion and that the nuclear localization of TDP-43 is lost in the islets of autopsied ALS pancreas. Loss of TDP-43 inhibits exocytosis, thereby reducing early-phase insulin secretion in a cultured β cell line (MIN6). Using microarray analysis, we identified the genes causing insulin impaired in TDP knocked down MIN6 cells.