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CDC7 inhibition blocks pathological TDP‐43 phosphorylation and neurodegeneration
Author(s) -
Liachko Nicole F.,
McMillan Pamela J.,
Guthrie Chris R.,
Bird Thomas D.,
Leverenz James B.,
Kraemer Brian C.
Publication year - 2013
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.23870
Subject(s) - frontotemporal lobar degeneration , amyotrophic lateral sclerosis , neurodegeneration , phosphorylation , kinase , biology , frontotemporal dementia , neuroscience , microbiology and biotechnology , cancer research , medicine , pathology , disease , dementia
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