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Dual phosphorylation of TDP\u201043 at serines 409\/410 (S409\/410) drives neurotoxicity in disease models; therefore, TDP\u201043\u2013specific kinases are candidate targets for intervention.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To find therapeutic targets for the prevention of TDP\u201043 phosphorylation, we assembled and screened a comprehensive RNA interference library targeting kinases in TDP\u201043 transgenic <jats:italic>Caenorhabditis elegans<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We show CDC7 robustly phosphorylates TDP\u201043 at pathological residues S409\/410 in <jats:italic>C. elegans<\/jats:italic>, in vitro, and in human cell culture. In frontotemporal lobar degeneration (FTLD)\u2010TDP cases, CDC7 immunostaining overlaps with the phospho\u2013TDP\u201043 pathology found in frontal cortex. Furthermore, PHA767491, a small molecule inhibitor of CDC7, reduces TDP\u201043 phosphorylation and prevents TDP\u201043\u2013dependent neurodegeneration in TDP\u201043\u2013transgenic animals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Taken together, these data support CDC7 as a novel therapeutic target for TDP\u201043 proteinopathies, including FTLD\u2010TDP and amyotrophic lateral sclerosis. 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