Here we report, for the first time, that neuronal inhibition of NF-κB signaling by expression of IκB-SR was able to mitigate the cytoplasmic TDP-43 proteinopathy and behavioral deficits in transgenic models of ALS/FTLD overexpressing TDP-43A315T or TDP-43G348C mutants. The gene discussed is TARDBP; the disease is amyotrophic lateral sclerosis.