CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegeneration
Article first published online: 8 JUL 2013
Copyright © 2013 American Neurological Association
Annals of Neurology
Volume 74, Issue 1, pages 39–52, July 2013
How to Cite
Liachko, N. F., McMillan, P. J., Guthrie, C. R., Bird, T. D., Leverenz, J. B. and Kraemer, B. C. (2013), CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegeneration. Ann Neurol., 74: 39–52. doi: 10.1002/ana.23870
- Issue published online: 27 AUG 2013
- Article first published online: 8 JUL 2013
- Accepted manuscript online: 19 FEB 2013 09:42AM EST
- Manuscript Accepted: 25 JAN 2013
- Manuscript Revised: 14 DEC 2012
- Manuscript Received: 28 AUG 2012
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. Ann Neurol 2013;74:39–52