Altered tubulin detyrosination due to SVBP malfunction induces cytokinesis failure and senescence, underlying a complex hereditary spastic paraplegia

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dc.contributor.authorLaunay, Nathalie
dc.contributor.author Espinosa Alcantud, Maria Dolores
dc.contributor.authorVerdura, Edgar
dc.contributor.authorFernández García de Eulate, Gorka
dc.contributor.authorOndaro Ezkurra, Jon
dc.contributor.authorIruzubieta Agudo, Pablo
dc.contributor.authorMarsal Terés, María
dc.contributor.authorSchlüter, Agatha
dc.contributor.authorRuiz Sales, Montserrat
dc.contributor.authorFourcade, Stèphane
dc.contributor.authorRodríguez-Palmero Seuma, Agustí
dc.contributor.authorZulaica, Miren
dc.contributor.authorSistiaga Berrondo, Andone
dc.contributor.authorLabayru, Garazi
dc.contributor.authorLoza-Alvarez, Pablo
dc.contributor.authorVaquero, Alejandro
dc.contributor.authorLópez de Munain Arregui, Adolfo
dc.contributor.authorPujol, Aurora
dc.date.accessioned2025-02-17T12:04:11Z
dc.date.available2025-02-17T12:04:11Z
dc.date.issued2025-01
dc.date.updated2025-02-17T12:04:11Z
dc.description.abstractSenescence, marked by permanent cell cycle arrest may contribute to the decline in regenerative potential and neuronal function, thereby promoting neurodegenerative disorders. In this study, we employed whole exome sequencing to identify a previously unreported biallelic missense variant in SVBP (p.Leu49Pro) in six patients from three unrelated families. These affected individuals present with a complex hereditary spastic paraplegia (HSP), peripheral neuropathy, verbal apraxia, and intellectual disability, exhibiting a milder phenotype compared to patients with nonsense SVBP mutations described previously. Consistent with SVBP's primary role as a chaperone necessary for VASH-mediated tubulin detyrosination, both patient fibroblasts with the p.Leu49Pro mutation, and HeLa cells harboring an SVBP knockdown exhibit microtubule dynamic instability and alterations in pericentriolar material (PCM) component trafficking and centrosome cohesion. In patient fibroblasts, structural abnormalities in the centrosome trigger mitotic errors and cellular senescence. Notably, premature senescence characterized by elevated levels of p16INK4, was also observed in patient peripheral blood mononuclear cells (PBMCs). Taken together, our findings underscore the critical role of SVBP in the development and maintenance of the central nervous system, providing novel insights associating cytokinesis failure with cortical motor neuron disease and intellectual disability.en
dc.description.sponsorshipthe Spanish Ministry of Economy and Competitiveness MINECO, Grant/Award Number: BES-2015-071251, PID2020-117284RB-100 and SEV-2015-0522; Association ASL-HSP and ‘La Marató de TV3’ Foundation, Grant/Award Number: 202006-30; Instituto de Salud Carlos III, Grant/Award Number: CD19/00221 and Miguel Servet program CP11/00080; Fundación Hesperia and Secretariat for Universities and Research of the Ministry of Business and Knowledge of the Government of Catalonia, Grant/Award Number: 2017SGR1206; URDcat programme, Grant/Award Number: PERIS SLT002/16/00174; Centre for Biomedical Research on Rare Diseases (CIBERER), Grant/Award Number: ACCI19-759; Catalan government agency AGAUR, Grant/Award Number: AGAUR 2021-SGR-01378en
dc.identifier.citationLaunay, N., Espinosa-Alcantud, M., Verdura, E., Fernández-Eulate, G., Ondaro, J., Iruzubieta, P., Marsal, M., Schlüter, A., Ruiz, M., Fourcade, S., Rodríguez-Palmero, A., Zulaica, M., Sistiaga, A., Labayru, G., Loza-Alvarez, P., Vaquero, A., Lopez de Munain, A., & Pujol, A. (2025). Altered tubulin detyrosination due to SVBP malfunction induces cytokinesis failure and senescence, underlying a complex hereditary spastic paraplegia. Aging Cell, 24(1). https://doi.org/10.1111/ACEL.14355
dc.identifier.doi10.1111/ACEL.14355
dc.identifier.eissn1474-9726
dc.identifier.issn1474-9718
dc.identifier.urihttps://hdl.handle.net/20.500.14454/2315
dc.language.isoeng
dc.publisherJohn Wiley and Sons Inc
dc.rights© 2024 The Author(s)
dc.subject.otherCentrosome
dc.subject.otherCytokinesis failure
dc.subject.otherHSP
dc.subject.otherMicrotubule detyrosination
dc.subject.otherSenescence
dc.subject.otherSVBP
dc.titleAltered tubulin detyrosination due to SVBP malfunction induces cytokinesis failure and senescence, underlying a complex hereditary spastic paraplegiaen
dc.typejournal article
dcterms.accessRightsopen access
oaire.citation.issue1
oaire.citation.titleAging Cell
oaire.citation.volume24
oaire.licenseConditionhttps://creativecommons.org/licenses/by/4.0/
oaire.versionVoR
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