RTP801 mediates transneuronal toxicity in culture via extracellular vesicles

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dc.contributor.authorSolana-Balaguer, Júlia
dc.contributor.authorMartín-Flores, Núria
dc.contributor.authorGarcía-Segura, Pol
dc.contributor.authorCampoy-Campos, Genís
dc.contributor.authorPérez-Sisqués, Leticia
dc.contributor.authorChicote-González, Almudena
dc.contributor.authorFernández Irigoyen, Joaquín
dc.contributor.authorSantamaría Martínez, Enrique
dc.contributor.authorPérez-Navarro, Esther
dc.contributor.authorAlberch, Jordi
dc.contributor.authorMalagelada, Cristina
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.date.accessioned2024-05-07T14:21:40Z
dc.date.available2024-05-07T14:21:40Z
dc.date.issued2023
dc.date.updated2024-05-07T13:34:04Z
dc.description.abstractExtracellular vesicles (EVs) play a crucial role in intercellular communication, participating in the paracrine trophic support or in the propagation of toxic molecules, including proteins. RTP801 is a stress-regulated protein, whose levels are elevated during neurodegeneration and induce neuron death. However, whether RTP801 toxicity is transferred trans-neuronally via EVs remains unknown. Hence, we overexpressed or silenced RTP801 protein in cultured cortical neurons, isolated their derived EVs (RTP801-EVs or shRTP801-EVs, respectively), and characterized EVs protein content by mass spectrometry (MS). RTP801-EVs toxicity was assessed by treating cultured neurons with these EVs and quantifying apoptotic neuron death and branching. We also tested shRTP801-EVs functionality in the pathologic in vitro model of 6-Hydroxydopamine (6-OHDA). Expression of RTP801 increased the number of EVs released by neurons. Moreover, RTP801 led to a distinct proteomic signature of neuron-derived EVs, containing more pro-apoptotic markers. Hence, we observed that RTP801-induced toxicity was transferred to neurons via EVs, activating apoptosis and impairing neuron morphology complexity. In contrast, shRTP801-EVs were able to increase the arborization in recipient neurons. The 6-OHDA neurotoxin elevated levels of RTP801 in EVs, and 6-OHDA-derived EVs lost the mTOR/Akt signalling activation via Akt and RPS6 downstream effectors. Interestingly, EVs derived from neurons where RTP801 was silenced prior to exposing them to 6-OHDA maintained Akt and RPS6 transactivation in recipient neurons. Taken together, these results suggest that RTP801-induced toxicity is transferred via EVs, and therefore, it could contribute to the progression of neurodegenerative diseases, in which RTP801 is involved.en
dc.description.sponsorshipSupported in part by grants from Ministerio de Ciencia e Innovación /AEI/10.13039/501100011033/ and ‘FEDER’: SAF2017-88812-R and PID2020-119236RB-I00, from CM; PID2020-119386RB-I00 from JA and PID2019-106447RB-I00 from EP-N. JS-B was supported by a FPU grant from the Spanish Ministry of Science and Innovation (grant #FPU18/00194). NM-F was supported by a FPI grant from the Spanish Ministry of Science and Innovation (grant IBES-2015-072727). PG-S was supported by a FPU grant from the Spanish Ministry of Science and Innovation (grant #FPU21/02928). GC-C was funded by a FI-2021 grant from the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (grant #FI-B-00378). AC-G was supported by a Michael J. Fox Foundation grant (MJFF-000858). Supported also bythe crowdfunding campaign ‘SOS recerca en Parkinson’ via Goteo.org and Portal d’Avall, S.L.en
dc.format.mimetypeapplication/pdfen
dc.identifier.citationSolana-Balaguer, J., Martín-Flores, N., Garcia-Segura, P., Campoy-Campos, G., Pérez-Sisqués, L., Chicote-González, A., Fernández-Irigoyen, J., Santamaría, E., Pérez-Navarro, E., Alberch, J., Malagelada, C. (2023) RTP801 mediates transneuronal toxicity in culture via extracellular vesicles. Journal of Extracellular Vesicles, 12(11), 1-26. https://doi.org/10.1002/jev2.12378.en
dc.identifier.doi10.1002/jev2.12378
dc.identifier.issn2001-3078
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/48057
dc.language.isoengen
dc.publisherWileyen
dc.relation.ispartofJournal of Extracellular Vesicles 2023, 12(11), 12378en
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-88812-R/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-119236RB-I00/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-119386RB-I00/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-106447RB-I00/ES/
dc.relation.publisherversionhttps://doi.org/10.1002/jev2.12378
dc.rights© 2023 The Authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivsLicense, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.en
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject6-OHDAen
dc.subjectExtracellular vesiclesen
dc.subjectmTOR signallingen
dc.subjectNeuronen
dc.subjectRTP801/REDD1en
dc.subjectToxicityen
dc.titleRTP801 mediates transneuronal toxicity in culture via extracellular vesiclesen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublication86d1b76e-4790-40b1-a3ec-72331c5c6199
relation.isAuthorOfPublicationabacfd17-2b93-4d99-bae2-52053d57401e
relation.isAuthorOfPublication.latestForDiscovery86d1b76e-4790-40b1-a3ec-72331c5c6199

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