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Depletion of Progranulin Reduces GluN2B-Containing NMDA Receptor Density, Tau Phosphorylation, and Dendritic Arborization in Mouse Primary Cortical Neurons.
Longhena, Francesca; Zaltieri, Michela; Grigoletto, Jessica; Faustini, Gaia; La Via, Luca; Ghidoni, Roberta; Benussi, Luisa; Missale, Cristina; Spano, PierFranco; Bellucci, Arianna.
Afiliación
  • Longhena F; Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (F.L, M.Z., J.G., G.F., L.L.V., C.M., P.S., A.B.) and Molecular Markers Laboratory, IRCCS Instituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy (R.G., L.B.).
  • Zaltieri M; Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (F.L, M.Z., J.G., G.F., L.L.V., C.M., P.S., A.B.) and Molecular Markers Laboratory, IRCCS Instituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy (R.G., L.B.).
  • Grigoletto J; Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (F.L, M.Z., J.G., G.F., L.L.V., C.M., P.S., A.B.) and Molecular Markers Laboratory, IRCCS Instituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy (R.G., L.B.).
  • Faustini G; Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (F.L, M.Z., J.G., G.F., L.L.V., C.M., P.S., A.B.) and Molecular Markers Laboratory, IRCCS Instituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy (R.G., L.B.).
  • La Via L; Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (F.L, M.Z., J.G., G.F., L.L.V., C.M., P.S., A.B.) and Molecular Markers Laboratory, IRCCS Instituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy (R.G., L.B.).
  • Ghidoni R; Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (F.L, M.Z., J.G., G.F., L.L.V., C.M., P.S., A.B.) and Molecular Markers Laboratory, IRCCS Instituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy (R.G., L.B.).
  • Benussi L; Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (F.L, M.Z., J.G., G.F., L.L.V., C.M., P.S., A.B.) and Molecular Markers Laboratory, IRCCS Instituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy (R.G., L.B.).
  • Missale C; Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (F.L, M.Z., J.G., G.F., L.L.V., C.M., P.S., A.B.) and Molecular Markers Laboratory, IRCCS Instituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy (R.G., L.B.).
  • Spano P; Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (F.L, M.Z., J.G., G.F., L.L.V., C.M., P.S., A.B.) and Molecular Markers Laboratory, IRCCS Instituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy (R.G., L.B.).
  • Bellucci A; Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (F.L, M.Z., J.G., G.F., L.L.V., C.M., P.S., A.B.) and Molecular Markers Laboratory, IRCCS Instituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy (R.G., L.B.) arianna.bellucci@unibs.it.
J Pharmacol Exp Ther ; 363(2): 164-175, 2017 11.
Article en En | MEDLINE | ID: mdl-28899992
ABSTRACT
Loss-of-function mutations in the progranulin (PGRN) gene are a common cause of familial frontotemporal lobar degeneration (FTLD). This age-related neurodegenerative disorder, characterized by brain atrophy in the frontal and temporal lobes and such typical symptoms as cognitive and memory impairment, profound behavioral abnormalities, and personality changes is thought to be related to connectome dysfunctions. Recently, PGRN reduction has been found to induce a behavioral phenotype reminiscent of FTLD symptoms in mice by affecting neuron spine density and morphology, suggesting that the protein can influence neuronal structural plasticity. Here, we evaluated whether a partial haploinsufficiency-like PGRN depletion, achieved by using RNA interference in primary mouse cortical neurons, could modulate GluN2B-containing N-methyl-d-aspartate (NMDA) receptors and tau phosphorylation, which are crucially involved in the regulation of the structural plasticity of these cells. In addition, we studied the effect of PGRN decrease on neuronal cell arborization both in the presence and absence of GluN2B-containing NMDA receptor stimulation. We found that PGRN decline diminished GluN2B-containing NMDA receptor levels and density as well as NMDA-dependent tau phosphorylation. These alterations were accompanied by a marked drop in neuronal arborization that was prevented by an acute GluN2B-containing NMDA receptor stimulation. Our findings support that PGRN decrease, resulting from pathogenic mutations, might compromise the trophism of cortical neurons by affecting GluN2B-contaning NMDA receptors. These mechanisms might be implicated in the pathogenesis of FTLD.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Corteza Cerebral / Proteínas tau / Receptores de N-Metil-D-Aspartato / Péptidos y Proteínas de Señalización Intercelular / Interferencia de ARN / Plasticidad Neuronal / Neuronas Límite: Animals Idioma: En Revista: J Pharmacol Exp Ther Año: 2017 Tipo del documento: Article

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Corteza Cerebral / Proteínas tau / Receptores de N-Metil-D-Aspartato / Péptidos y Proteínas de Señalización Intercelular / Interferencia de ARN / Plasticidad Neuronal / Neuronas Límite: Animals Idioma: En Revista: J Pharmacol Exp Ther Año: 2017 Tipo del documento: Article