CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegeneration.

Abstract

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. 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. 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. Taken together, these data support CDC7 as a novel therapeutic target for TDP-43 proteinopathies, including FTLD-TDP and amyotrophic lateral sclerosis.