The therapeutic benefits of Nlk reduction on motor behavior, neurodegeneration and its associated astrogliosis, and survival of 2 independent TDP-43 animal models provide strong proof-of-principle evidence for this approach in TDP-43 proteinopathies, both in instances in which TARDBP mutations are present (a subset of ALS patients) and when TARDBP mutations are not present but TDP-43 aggregation occurs. Here, NLK is linked to proteostasis deficiencies.