Thus, for an understanding of the pathogenesis of ALS associated with TDP-43 aggregation, it is imperative to fully figure out the functions and regulation of TDP-43-containing RNP complexes that assemble in the normal physiological conditions, investigate the nature of pathological changes occurring in wild-type TDP-43, and explore upstream intracellular and extracellular factors that promote the pathological transition of TDP-43 in motor neurons in vivo (Fig. 1). Here, TARDBP is linked to amyotrophic lateral sclerosis.