Overall, our results reveal a novel shared mechanism of pathogenesis for misfolded aggregates of TDP-43 and FUS mediated by interference with protein translation in a RACK1-dependent manner and provide proof-of-concept evidence for targeting RACK1 as a therapeutic approach for TDP-43 or FUS proteinopathy associated with ALS and FTLD. Here, TARDBP is linked to amyotrophic lateral sclerosis.