Targeting TDP-43 phosphorylation by Casein Kinase-1δ inhibitors: a novel strategy for the treatment of frontotemporal dementia

Mol Neurodegener. 2016 Apr 30;11(1):36. doi: 10.1186/s13024-016-0102-7.


Background: Mutations in the progranulin gene (GRN) are the most common cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). TDP-43 pathology is characterized by the hyperphosphorylation of the protein at Serine 409/410 residues. Casein kinase-1δ (CK-1δ) was reported to phosphorylate TDP-43 directly. Previous works from our laboratory described the presence of CDK6/pRb-dependent cell cycle alterations, and cytosolic accumulation of TDP-43 protein in lymphoblast from FTLD-TDP patients carriers of a loss-of function mutation in GRN gene (c.709-1G > A). In this work, we have investigated the effects of two brain penetrant CK-1δ inhibitors (IGS-2.7 and IGS-3.27) designed and synthetized in our laboratory on cell proliferation, TDP-43 phosphorylation and subcellular localization, as well as their effects on the known nuclear TDP-43 function repressing the expression of CDK6.

Results: We report here that both CK-1δ inhibitors (IGS-2.7 and IGS-3.27) normalized the proliferative activity of PGRN-deficient lymphoblasts by preventing the phosphorylation of TDP-43 fragments, its nucleo-cytosol translocation and the overactivation of the CDK6/pRb cascade. Moreover, ours results show neuroprotective effects of CK-1δ inhibitors in a neuronal cell model of induced TDP-43 phosphorylation.

Conclusions: Our results suggest that modulating CK-1δ activity could be considered a novel therapeutic approach for the treatment of FTLD-TDP and other TDP-43 proteinopathies.

Keywords: CDK6; CK-1δ; Cell proliferation; FTLD-TDP; Lymphocytes; TDP-43.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Casein Kinase Idelta / antagonists & inhibitors*
  • Casein Kinase Idelta / metabolism
  • Cell Proliferation / physiology*
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • Frontotemporal Dementia / drug therapy
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / metabolism*
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Lymphocytes / metabolism
  • Mutation / genetics
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology*
  • TDP-43 Proteinopathies / metabolism*


  • DNA-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • Casein Kinase Idelta