Examinando por Autor "Verdura, Edgar"

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    Altered tubulin detyrosination due to SVBP malfunction induces cytokinesis failure and senescence, underlying a complex hereditary spastic paraplegia
    (John Wiley and Sons Inc, 2025-01) Launay, Nathalie; Espinosa Alcantud, Maria Dolores; Verdura, Edgar; Fernández García de Eulate, Gorka; Ondaro Ezkurra, Jon; Iruzubieta Agudo, Pablo; Marsal Terés, María; Schlüter, Agatha; Ruiz Sales, Montserrat; Fourcade, Stèphane; Rodríguez-Palmero Seuma, Agustí; Zulaica, Miren; Sistiaga Berrondo, Andone; Labayru, Garazi; Loza-Alvarez, Pablo; Vaquero, Alejandro; López de Munain Arregui, Adolfo; Pujol, Aurora
    Senescence, 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.