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Stabilization of 14-3-3 protein-protein interactions with Fusicoccin-A decreases alpha-synuclein dependent cell-autonomous death in neuronal and mouse models
dc.creator | Vinueza-Gavilanes, Rodrigo | es_ES |
dc.creator | Bravo-González, Jorge Juan | es_ES |
dc.creator | Basurco, Leyre | es_ES |
dc.creator | Boncristiani, Chiara | es_ES |
dc.creator | Fernández Irigoyen, Joaquín | es_ES |
dc.creator | Santamaría, Enrique | es_ES |
dc.creator | Marcilla, Irene | es_ES |
dc.creator | Pérez Mediavilla, Alberto | es_ES |
dc.creator | Luquin, María Rosario | es_ES |
dc.creator | Vales, Africa | es_ES |
dc.creator | González-Aseguinolaza, Gloria | es_ES |
dc.creator | Aymerich, María Soledad | es_ES |
dc.creator | Aragón, Tomás | es_ES |
dc.creator | Arrasate, Montserrat | es_ES |
dc.date.accessioned | 2023-10-16T15:34:27Z | |
dc.date.available | 2023-10-16T15:34:27Z | |
dc.date.issued | 2023 | |
dc.identifier.citation | Vinueza-Gavilanes, R., Bravo-González, J. J., Basurco, L., Boncristiani, C., Fernández-Irigoyen, J., Santamaría, E., Marcilla, I., Pérez-Mediavilla, A., Luquin, M. R., Vales, A., González-Aseguinolaza, G., Aymerich, M. S., Aragón, T., Arrasate, M. (2023) Stabilization of 14-3-3 protein-protein interactions with Fusicoccin-A decreases alpha-synuclein dependent cell-autonomous death in neuronal and mouse models. Neurobiology of Disease, 183, 1-15. https://doi.org/10.1016/j.nbd.2023.106166. | en |
dc.identifier.issn | 0969-9961 | |
dc.identifier.uri | https://hdl.handle.net/2454/46530 | |
dc.description.abstract | Synucleinopathies are a group of neurodegenerative diseases without effective treatment characterized by the abnormal aggregation of alpha-synuclein (aSyn) protein. Changes in levels or in the amino acid sequence of aSyn (by duplication/triplication of the aSyn gene or point mutations in the encoding region) cause familial cases of synucleinopathies. However, the specific molecular mechanisms of aSyn-dependent toxicity remain unclear. Increased aSyn protein levels or pathological mutations may favor abnormal protein-protein interactions (PPIs) that could either promote neuronal death or belong to a coping response program against neurotoxicity. Therefore, the identification and modulation of aSyn-dependent PPIs can provide new therapeutic targets for these diseases. To identify aSyn-dependent PPIs we performed a proximity biotinylation assay based on the promiscuous biotinylase BioID2. When expressed as a fusion protein, BioID2 biotinylates by proximity stable and transient interacting partners, allowing their identification by streptavidin affinity purification and mass spectrometry. The aSyn interactome was analyzed using BioID2-tagged wild-type (WT) and pathological mutant E46K aSyn versions in HEK293 cells. We found the 14-3-3 epsilon isoform as a common protein interactor for WT and E46K aSyn. 14‐3-3 epsilon correlates with aSyn protein levels in brain regions of a transgenic mouse model overexpressing WT human aSyn. Using a neuronal model in which aSyn cell-autonomous toxicity is quantitatively scored by longitudinal survival analysis, we found that stabilization of 14‐3-3 protein-proteins interactions with Fusicoccin-A (FC-A) decreases aSyn-dependent toxicity. Furthermore, FC-A treatment protects dopaminergic neuronal somas in the substantia nigra of a Parkinson's disease mouse model. Based on these results, we propose that the stabilization of 14‐3-3 epsilon interaction with aSyn might reduce aSyn toxicity, and highlight FC-A as a potential therapeutic compound for synucleinopathies. | en |
dc.description.sponsorship | This work was supported by the Navarra Government (3/2019 , PC060-061 and PC192-193), the Spanish Government ISCIII-FEDER PI20/01063 and PI21/00259 and the Fundación para la Investigación Médica Aplicada (FIMA) . R.V-G was supported by a postdoctoral contract from the Navarra Government (PC192-193), J.B. by the Investigación Biomédica AC 2020 Predoctoral Fellowships from CIMA University of Navarra , C·B was supported by University of Milan with Students Erasmus+ Scholarships a.y. 2018/2019 and L. B. by a FPU predoctoral fellowship FPU018/02244 . | en |
dc.format.mimetype | application/pdf | en |
dc.language.iso | eng | en |
dc.publisher | Elsevier | en |
dc.relation.ispartof | Neurobiology of Disease 183 (2023) 106166 | en |
dc.rights | © 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license. | en |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
dc.subject | 14-3-3 epsilon | en |
dc.subject | Adenoassociated virus AAV9 | en |
dc.subject | Alpha-synuclein | en |
dc.subject | BioID2 | en |
dc.subject | Fusicoccin-A | en |
dc.subject | Longitudinal survival analysis | en |
dc.subject | Neuronal death | en |
dc.subject | Parkinson's disease | en |
dc.subject | Proximity biotinylation | en |
dc.subject | Synucleinopathies | en |
dc.title | Stabilization of 14-3-3 protein-protein interactions with Fusicoccin-A decreases alpha-synuclein dependent cell-autonomous death in neuronal and mouse models | en |
dc.type | Artículo / Artikulua | es |
dc.type | info:eu-repo/semantics/article | en |
dc.date.updated | 2023-10-16T14:43:06Z | |
dc.contributor.department | Ciencias de la Salud | es_ES |
dc.contributor.department | Osasun Zientziak | eu |
dc.rights.accessRights | Acceso abierto / Sarbide irekia | es |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | en |
dc.identifier.doi | 10.1016/j.nbd.2023.106166 | |
dc.relation.projectID | info:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI20%2F01063/ES/ | en |
dc.relation.projectID | info:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI21%2F00259/ES/ | en |
dc.relation.projectID | info:eu-repo/grantAgreement/Gobierno de Navarra//PC060-061 | en |
dc.relation.projectID | info:eu-repo/grantAgreement/Gobierno de Navarra//PC192-193 | en |
dc.relation.publisherversion | https://doi.org/10.1016/j.nbd.2023.106166 | |
dc.type.version | Versión publicada / Argitaratu den bertsioa | es |
dc.type.version | info:eu-repo/semantics/publishedVersion | en |