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Increased Wnt Signaling and Reduced Viability in a Neuronal Model of Progranulin-Deficient Frontotemporal Lobar Degeneration

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Abstract

Progranulin (PGRN) deficiency is considered the major cause of frontotemporal lobar degeneration with TDP-43 protein inclusions (FTLD-TDP). Recent work unveiled a relationship between Wnt signaling and PGRN in cellular models of FTLD and cells of patients carrying loss-of-function GRN mutations. This study was undertaken to explore the relationship between PGRN deficit and Wnt signaling in the regulation of survival of GRN knockdown neuroblastoma SH-SY5Y cells (GRN KD). We report here that both canonical and noncanonical Wnt signaling cascades are overactivated in GRN KD cells. We detected increased expression levels of Wnt1 and Wnt5a ligands of the Frizzled receptors, as well as evidence for increased signaling of the Wnt/β-catenin and Wnt/Ca2+ cascades in PGRN deficient cells, such as increased nuclear content of β-catenin and higher levels of cyclin D1, or increased levels of the active form of the NFAT1 transcription factor, respectively. Upregulation of either Wnt/β-catenin or Wnt/Ca2+ signaling in GRN KD cells leads to the stimulation of BrdU incorporation into DNA, hyperphosphorylation of the pRb family of proteins and reduced cell viability over time. Blocking the Wnt cascades by specific canonical or noncanonical inhibitors of Wnt-dependent signaling, normalized the rate of DNA synthesis, and what it is more important restored the viability of GRN KD cells. Our results suggest an important role of Wnt activation inducing cell cycle disturbance-mediated neuronal loss in the pathogenesis of PGRN deficiency-linked FTLD-TDP. Therefore, it is plausible that modulation of Wnt signaling could be a promising strategy for developing of new disease-modifying treatments for FTLD-TDP.

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Acknowledgments

This work has been supported by grants from the Ministerio de Economía y Competitividad (SAF2011-28603) and Fundación Ramón Areces. AdlE is supported by the Fundación Ramón Areces. We thank Drs. Joselin and Wu for providing the GRN KD SH-SY5Y cells. The skillful assistance of Haidée Aranda is greatly appreciated.

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Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC) Madrid, Madrid, Spain

    Ana de la Encarnación, Carolina Alquézar & Ángeles Martín-Requero

  2. CIBER de Enfermedades Raras (CIBERER), Madrid, Spain

    Ángeles Martín-Requero

  3. Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain

    Ángeles Martín-Requero

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  1. Ana de la Encarnación
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  2. Carolina Alquézar
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Correspondence to Ángeles Martín-Requero.

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de la Encarnación, A., Alquézar, C. & Martín-Requero, Á. Increased Wnt Signaling and Reduced Viability in a Neuronal Model of Progranulin-Deficient Frontotemporal Lobar Degeneration. Mol Neurobiol 53, 7107–7118 (2016). https://doi.org/10.1007/s12035-015-9596-1

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