Our finding that biochemical insolubility of TDP-43 correlates with splicing defects as well as with insolubility of several other RBPs casts doubt on the TDP-43-centric view of ALS (Lagier-Tourenne and Cleveland, 2009; Scotter et al., 2015). The gene discussed is TARDBP; the disease is amyotrophic lateral sclerosis.