Currently, the role of TDP-43 aggregates in neurodegenerative diseases is unknown and two hypotheses have been proposed (Lee et al., 2012): (1) the “gain-of-function” hypothesis, which suggests that cytoplasmic TDP-43 aggregates, or the presence of missense mutations in TDP-43, provokes cell death by cytotoxic effects (Johnson et al., 2008, 2009; Zhang et al., 2009); (2) the “loss-of-function” hypothesis, which suggests that TDP-43 aggregates act as a “sink” by additionally sequestering functional TDP-43 (nuclear and cytoplasmic). The gene discussed is TARDBP; the disease is neurodegenerative disease.