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CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegeneration

Nicole F Liachko1, Pamela J McMillan, Chris R Guthrie

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

Annals of Neurology
|February 21, 2013
PubMed
Abstract

Insights

CDC7 kinase phosphorylates TDP-43 at pathological sites, driving neurotoxicity. Inhibiting CDC7 reduces TDP-43 phosphorylation and prevents neurodegeneration, offering a therapeutic target for TDP-43 proteinopathies.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Kinase hyperactivity is implicated in neurodegenerative diseases and cancer.
  • TDP-43 pathology, specifically dual phosphorylation at S409/410, characterizes amyotrophic lateral sclerosis and frontotemporal lobar degeneration.
  • TDP-43 phosphorylation at S409/410 drives neurotoxicity, making TDP-43 kinases potential therapeutic targets.

Purpose of the Study:

  • To identify therapeutic targets for preventing TDP-43 phosphorylation.
  • To screen for kinases that phosphorylate TDP-43 using a comprehensive RNA interference library.

Main Methods:

  • Screened a kinase-targeting RNA interference library in TDP-43 transgenic Caenorhabditis elegans.
  • Investigated CDC7 kinase activity in TDP-43 phosphorylation in vitro and in human cell culture.
  • Examined CDC7 expression in human frontotemporal lobar degeneration (FTLD)-TDP cases and assessed the efficacy of a CDC7 inhibitor (PHA767491).

Main Results:

  • CDC7 was identified as a kinase that robustly phosphorylates TDP-43 at pathological S409/410 residues.
  • CDC7 immunostaining overlapped with phospho-TDP-43 pathology in FTLD-TDP frontal cortex.
  • The CDC7 inhibitor PHA767491 reduced TDP-43 phosphorylation and prevented TDP-43-dependent neurodegeneration in animal models.

Conclusions:

  • CDC7 is a novel therapeutic target for TDP-43 proteinopathies.
  • Targeting CDC7 may offer a treatment strategy for conditions like FTLD-TDP and amyotrophic lateral sclerosis.

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