title: PGRN haploinsufficiency increased Wnt5a signaling in peripheral cells from frontotemporal lobar degeneration-progranulin mutation carriers.
abstract: Loss-of-function progranulin (PGRN) mutations have been identified as the major cause of frontotemporal lobar degeneration with TDP-43 protein inclusions (FTLD-TDP). Previously, we reported cell cycle-related alterations in lymphoblasts from FTLD-TDP patients, carrying the c.709-1G>A null PGRN mutation, suggesting aberrant cell cycle activation in affected neurons. Here we report that PGRN haploinsufficiency activates the extracellular signal-regulated protein kinases 1 and 2 pathway in a Ca(2+), protein kinase C-dependent, and pertussis toxin-sensitive manner. Addition of exogenous PGRN or conditioned medium from control cells normalized the response of PGRN-deficient lymphoblasts to serum activation. Our data indicated that noncanonical Wnt5a signaling might be overactivated by PGRN deficiency. We detected increased cellular and secreted levels of Wnt5a in PGRN-deficient lymphoblasts associated with enhanced phosphorylated calmodulin kinase II. Moreover, treatment of control cells with exogenous Wingless-type 5a (Wnt5a)-activated Ca(2+)/calmodulin kinase II (CaMKII), increased extracellular signal-regulated protein kinases 1 and 2 activity and cell proliferation up to the levels found in c.709-1G>A carrier cells. PGRN knockdown SH-SY5Y neuroblastoma cells also show enhanced Wnt5a content and signaling. Taken together, our results revealed an important role of Wnt signaling in FTLD-TDP pathology and suggest a novel target for therapeutic intervention.
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas, Madrid, Spain; CIBER de Enfermedades Raras.
authors.forename: Carolina
authors.initials: C
authors.lastname: Alquézar
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas, Madrid, Spain.
authors.forename: Noemí
authors.initials: N
authors.lastname: Esteras
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: de la Encarnación
authors.affiliation: Neuroscience Area-Institute Biodonostia, San Sebastián, Spain; Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Neurodegenerativas.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Alzualde
authors.affiliation: Neuroscience Area-Institute Biodonostia, San Sebastián, Spain; Department of Neurology, Hospital Donostia, San Sebastián, Spain; Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Neurodegenerativas.
authors.forename: Fermín
authors.initials: F
authors.lastname: Moreno
authors.affiliation: Neuroscience Area-Institute Biodonostia, San Sebastián, Spain; Department of Neurology, Hospital Donostia, San Sebastián, Spain; Department of Neurosciences, University of Basque Country, San Sebastián, Spain; Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Neurodegenerativas.
authors.forename: Adolfo
authors.initials: A
authors.lastname: López de Munain
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas, Madrid, Spain; CIBER de Enfermedades Raras. Electronic address: amrequero@cib.csic.es.
authors.forename: Angeles
authors.initials: A
authors.lastname: Martín-Requero
mesh_terms: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D057174:Frontotemporal Lobar Degeneration / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics*; D008214:Lymphocytes / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009154:Mutation; D009474:Neurons / Q000473:pathology; D037342:Pertussis Toxin; D000077153:Progranulins; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000502:physiology*; D000071818:Wnt-5a Protein
chemical_list: D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D037342:Pertussis Toxin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: CDK6; Cell proliferation; FTLD-TDP; Lymphocytes; Pertussis toxin; Wnt5a signaling