The discovery of the cytoplasmically localized sTDP-43 (Weskamp et al., 2020), the increased availability of endogenously tagged TDP-43 models, and higher resolution imaging technologies, may help overcome this barrier and lead to a better understanding of the mechanistic differences between healthy and degenerating neurons that could in turn uncover novel therapeutic strategies for ALS and related neurodegenerative disorders. Here, TARDBP is linked to amyotrophic lateral sclerosis.