These results demonstrate that a deficiency in DCTN1 and other microtubule-associated motor proteins drives the aggregation of wild-type TDP-43 through the dysregulation of stress granule dynamics, indicating the crucial role of intracellular transport along microtubules in the pathological development of the TDP-43 proteinopathies, including ALS/FTD. Here, DCTN1 is linked to proteostasis deficiencies.