TARDBP and amyotrophic lateral sclerosis: In motor neurons of ALS patients and model systems, depletion of TDP-43 in the nucleus (loss of function) and accumulation of TDP-43 in the cytoplasm (gain of toxicity)—both of which increase the Cyt/Nuc ratio of TDP-43—are crucial pathological features (Neumann et al., 2006; Hergesheimer et al., 2019).