Hence, it has been proposed that TDP-43 and FUS proteinopathies could either originate from a loss-of-function mechanism (resulting from clearance of functional RBPs from the nucleus), a gain-of-toxicity mechanism (resulting from aberrant accumulation of pathological RBP aggregates in the cytoplasm), or a combination of both (Fig. 5A). The gene discussed is TARDBP; the disease is proteostasis deficiencies.