Mislocalization of TDP-43 is thought to be an initiating step in the pathogenesis of ALS, yet the cause of TDP-43 nuclear depletion to this point was unclear11; our results indicate that aging is sufficient to cause TDP-43 mislocalization, which may act as the first insult driving neurons toward neurodegeneration. Here, TARDBP is linked to amyotrophic lateral sclerosis.