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CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegeneration

Authors

  • Nicole F. Liachko PhD,

    1. Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA
    2. Department of Medicine, University of Washington, Seattle, WA
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  • Pamela J. McMillan PhD,

    1. Mental Illness Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA
    2. Department of Psychiatry and Behavioral Sciences, Seattle, WA
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  • Chris R. Guthrie PhD,

    1. Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA
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  • Thomas D. Bird MD,

    1. Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA
    2. Department of Medicine, University of Washington, Seattle, WA
    3. Department of Neurology, University of Washington, Seattle, WA
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  • James B. Leverenz MD,

    1. Mental Illness Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA
    2. Department of Psychiatry and Behavioral Sciences, Seattle, WA
    3. Department of Neurology, University of Washington, Seattle, WA
    4. Parkinson's Disease Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA
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  • Brian C. Kraemer PhD

    Corresponding author
    1. Department of Medicine, University of Washington, Seattle, WA
    • Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA
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Address correspondence to Dr Kraemer, Veterans Affairs Puget Sound Health Care System, S182, 1660 South Columbian Way, Seattle, WA 98108. E-mail: kraemerb@u.washington.edu

Abstract

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

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