CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegeneration

Objective Kinase hyperactivity occurs in both neurodegenerative disease and cancer. Lesions containing hyperphosphorylated aggregated TDP‐43 characterize amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP‐43 inclusions. Dual phosphorylation of TDP‐43 at serines 409/410 (S409/410) drives neurotoxicity in disease models; therefore, TDP‐43–specific kinases are candidate targets for intervention. Methods To find therapeutic targets for the prevention of TDP‐43 phosphorylation, we assembled and screened a comprehensive RNA interference library targeting kinases in TDP‐43 transgenic Caenorhabditis elegans. Results We show CDC7 robustly phosphorylates TDP‐43 at pathological residues S409/410 in C. elegans, in vitro, and in human cell culture. In frontotemporal lobar degeneration (FTLD)‐TDP cases, CDC7 immunostaining overlaps with the phospho–TDP‐43 pathology found in frontal cortex. Furthermore, PHA767491, a small molecule inhibitor of CDC7, reduces TDP‐43 phosphorylation and prevents TDP‐43–dependent neurodegeneration in TDP‐43–transgenic animals. Interpretation Taken together, these data support CDC7 as a novel therapeutic target for TDP‐43 proteinopathies, including FTLD‐TDP and amyotrophic lateral sclerosis. Ann Neurol 2013;74:39–52