title: Targeting TDP-43 phosphorylation by Casein Kinase-1δ inhibitors: a novel strategy for the treatment of frontotemporal dementia.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Alquezar
authors.affiliation: Department of Chemical and Physical Biology, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.
authors.forename: Irene G
authors.initials: IG
authors.lastname: Salado
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: de la Encarnación
authors.affiliation: Department of Chemical and Physical Biology, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Pérez
authors.affiliation: Neuroscience Area-Institute Biodonostia, San Sebastian, Spain.
authors.forename: Fermín
authors.initials: F
authors.lastname: Moreno
authors.affiliation: Department of Chemical and Physical Biology, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Gil
authors.affiliation: Neuroscience Area-Institute Biodonostia, San Sebastian, Spain.|Department of Neurology, Hospital Donostia, San Sebastian, Spain.|Department of Neurosciences, University of Basque Country, San Sebastián, Spain.|CIBER de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Adolfo López
authors.initials: AL
authors.lastname: de Munain
authors.affiliation: Department of Chemical and Physical Biology, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain. ana.martinez@csic.es.
authors.forename: Ana
authors.initials: A
authors.lastname: Martínez
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain. amrequero@cib.csic.es.|CIBER de Enfermedades Raras (CIBERER), Madrid, Spain. amrequero@cib.csic.es.
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Martín-Requero
mesh_terms: D048148:Casein Kinase Idelta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D057180:Frontotemporal Dementia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008214:Lymphocytes / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D057177:TDP-43 Proteinopathies / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D048148:Casein Kinase Idelta
keywords: CDK6; CK-1δ; Cell proliferation; FTLD-TDP; Lymphocytes; TDP-43