pha-767491 and TDP-43-Proteinopathies

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.

Topics: Animals; Animals, Genetically Modified; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cell Cycle Proteins; Cell Line, Transformed; Disease Models, Animal; DNA-Binding Proteins; Enzyme Inhibitors; Frontal Lobe; Gene Expression Regulation; Humans; Movement; Mutation; Neurodegenerative Diseases; Phosphorylation; Piperidones; Protein Serine-Threonine Kinases; Pyrroles; RNA, Small Interfering; Serine; TDP-43 Proteinopathies; Transfection