These two hallmarks suggested that TDP-43 proteinopathies arise from either a loss of function, by impairing the normal function of nuclear TDP-43 in regulating transcription and mRNA processing, or a gain of toxicity of the cytosolic fraction of the protein, or both (Lee et al., 2012; Cascella et al., 2016). Here, TARDBP is linked to proteostasis deficiencies.