SigR1 agonists such as PRE084 have already been shown to reduce protein aggregation and ER stress11 and to be neuroprotective.15 Thus, our data suggest that the ALS proteins SigR1, TDP-43 and matrin-3 are interdependent in regulating cellular protein quality control pathways and that dysregulation of the RBPs matrin-3, FUS and TDP-43 can be directly caused by mSigR1 aggregation. Here, MATR3 is linked to amyotrophic lateral sclerosis.