NGF upregulates the plasminogen activation inhibitor-1 in neurons via the calcineurin/NFAT pathway and the down syndrome-related proteins DYRK1A and RCAN1 attenuate this effect

Mostra el registre complet Registre parcial de l'ítem

• dc.contributor.author Stefos, Georgios C.
• dc.contributor.author Soppa, Ulf
• dc.contributor.author Dierssen Sotos, Mara
• dc.contributor.author Becker, Walter
• dc.date.accessioned 2024-10-21T06:20:37Z
• dc.date.available 2024-10-21T06:20:37Z
• dc.date.issued 2013
• dc.description.abstract Background. Plasminogen activator inhibitor 1 (PAI-1) is a key regulator of the plasminogen activation system. Although several lines of evidence support a significant role of PAI-1 in the brain, the regulation of its expression in neurons is poorly understood. In the present study we tested the hypothesis that NGF induces the upregulation of PAI-1 via the calcineurin/nuclear factor of activated T cells (NFAT) pathway and analysed whether the overexpression of the Down syndrome-related proteins DYRK1A and RCAN1 modulated the effect of NGF on PAI-1 expression. Results. NGF upregulated PAI-1 mRNA levels in primary mouse hippocampal neurons cultured for 3 days in vitro and in the rat pheochromocytoma cell line PC12. Reporter gene assays revealed that NGF activated the calcineurin/NFAT pathway in PC12 cells. Induction of PAI-1 by NGF was sensitive to the calcineurin inhibitor FK506 and the specific inhibition of NFAT activation by the cell permeable VIVIT peptide. Activation of calcineurin/NFAT signalling through other stimuli resulted in a much weaker induction of PAI-1 expression, suggesting that other NGF-induced pathways are involved in PAI-1 upregulation. Overexpression of either DYRK1A or RCAN1 negatively regulated NFAT-dependent transcriptional activity and reduced the upregulation of PAI-1 levels by NGF. Conclusion. The present results show that the calcineurin/NFAT pathway mediates the upregulation of PAI-1 by NGF. The negative effect of DYRK1A and RCAN1 overexpression on NGF signal transduction in neural cells may contribute to the altered neurodevelopment and brain function in Down syndrome.
• dc.description.sponsorship This work was supported by grants from the Alexander von Humboldt Stiftung, Germany (GCS), the Jérôme Lejeune Foundation, France (WB), the Spanish Ministry of Science and Innovation SAF2010-16427 (MD), the European Union CureFXS ERare- FIS PS09102673 (MD) and the Friedrich-Naumann-Foundation, Germany (US). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• dc.format.mimetype application/pdf
• dc.identifier.citation Stefos GC, Soppa U, Dierssen M, Becker W. NGF upregulates the plasminogen activation inhibitor-1 in neurons via the calcineurin/NFAT pathway and the down syndrome-related proteins DYRK1A and RCAN1 attenuate this effect. PLoS ONE. 2013 Jun 25;8(6):e67470. DOI: 10.1371/journal.pone.0067470
• dc.identifier.doi http://dx.doi.org/10.1371/journal.pone.0067470
• dc.identifier.issn 1932-6203
• dc.identifier.uri http://hdl.handle.net/10230/68243
• dc.language.iso eng
• dc.publisher Public Library of Science (PLoS)
• dc.relation.ispartof PLoS ONE. 2013 Jun 25;8(6):e67470
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2010-16427
• dc.rights © 2013 Stefos et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.other Hipocamp
• dc.subject.other Fosforilació
• dc.subject.other Down, Síndrome de
• dc.title NGF upregulates the plasminogen activation inhibitor-1 in neurons via the calcineurin/NFAT pathway and the down syndrome-related proteins DYRK1A and RCAN1 attenuate this effect
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion