Using these TDP-43 biosensors we screenedthe 2,684-compound FDA-approvedSelleck library, and the hit compound ketoconazole – a knownP450 cytochrome inhibitor – is shown to increase NTD-dependentTDP-43 FRET and rescue a series of TDP-43 proteinopathy phenotypesin both cellular and in vivo models. Here, TARDBP is linked to proteostasis deficiencies.