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

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

Author information

1
Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.
2
Department of Chemical and Physical Biology, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.
3
Neuroscience Area-Institute Biodonostia, San Sebastian, Spain.
4
Department of Neurology, Hospital Donostia, San Sebastian, Spain.
5
Department of Neurosciences, University of Basque Country, San Sebastián, Spain.
6
CIBER de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
7
Department of Chemical and Physical Biology, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain. ana.martinez@csic.es.
8
Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain. amrequero@cib.csic.es.
9
CIBER de Enfermedades Raras (CIBERER), Madrid, Spain. amrequero@cib.csic.es.

Abstract

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

PMID:
27138926
PMCID:
PMC4852436
DOI:
10.1186/s13024-016-0102-7
[Indexed for MEDLINE]
Free PMC Article

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