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

Autor: Launay N; Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain.; Center for Biomedical Research on Rare Diseases, (CIBERER U759) Ministry of Science Innovation and University, Madrid, Spain., Espinosa-Alcantud M; Chromatin Biology Laboratory, Josep Carreras Leukaemia Research Institute, Badalona, Spain., Verdura E; Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain., Fernández-Eulate G; Nord-Est/Ile-de-France Neuromuscular Reference Center, Institute of Myology, Pitié-Salpêtrière Hospital, Paris, France.; Department of Neurology, Hospital Universitario Donostia, OSAKIDETZA-Department of Neurosciences, University of the Basque Cpuntry, San Sebastian, Spain., Ondaro J; Department of Neurosciences, Instituto Biodonostia, San Sebastián, Spain.; Center of Biomedical Research in Neurodegenerative Diseases (CIBERNED), CIBER, Ministry of Science, Innovation and University, Madrid, Spain., Iruzubieta P; Department of Neurology, Hospital Universitario Donostia, OSAKIDETZA-Department of Neurosciences, University of the Basque Cpuntry, San Sebastian, Spain.; Department of Neurosciences, Instituto Biodonostia, San Sebastián, Spain.; Center of Biomedical Research in Neurodegenerative Diseases (CIBERNED), CIBER, Ministry of Science, Innovation and University, Madrid, Spain.; Department of Medicine, School of Medicine, University of Deusto, Bilbao, Spain., Marsal M; ICFO-Institut de Ciencies Fotoniques, The Barcelona Institute of Science and Technology, Castelldefels, Spain., Schlüter A; Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain., Ruiz M; Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain.; Center for Biomedical Research on Rare Diseases, (CIBERER U759) Ministry of Science Innovation and University, Madrid, Spain., Fourcade S; Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain.; Center for Biomedical Research on Rare Diseases, (CIBERER U759) Ministry of Science Innovation and University, Madrid, Spain., Rodríguez-Palmero A; Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain.; Center for Biomedical Research on Rare Diseases, (CIBERER U759) Ministry of Science Innovation and University, Madrid, Spain.; Pediatric Neurology Unit, Department of Pediatrics, University Hospital Germans Trias i Pujol, Autonomous University of Barcelona, Badalona, Spain., Zulaica M; Department of Neurosciences, Instituto Biodonostia, San Sebastián, Spain., Sistiaga A; Center of Biomedical Research in Neurodegenerative Diseases (CIBERNED), CIBER, Ministry of Science, Innovation and University, Madrid, Spain.; Department of Personality, Assessment and Psychological Treatment Faculty of Psychology, University of the Basque Country (UPV/EHU), San Sebastian, Spain., Labayru G; Center of Biomedical Research in Neurodegenerative Diseases (CIBERNED), CIBER, Ministry of Science, Innovation and University, Madrid, Spain.; Department of Personality, Assessment and Psychological Treatment Faculty of Psychology, University of the Basque Country (UPV/EHU), San Sebastian, Spain., Loza-Alvarez P; ICFO-Institut de Ciencies Fotoniques, The Barcelona Institute of Science and Technology, Castelldefels, Spain., Vaquero A; Chromatin Biology Laboratory, Josep Carreras Leukaemia Research Institute, Badalona, Spain., Lopez de Munain A; Department of Neurology, Hospital Universitario Donostia, OSAKIDETZA-Department of Neurosciences, University of the Basque Cpuntry, San Sebastian, Spain.; Department of Neurosciences, Instituto Biodonostia, San Sebastián, Spain.; Center of Biomedical Research in Neurodegenerative Diseases (CIBERNED), CIBER, Ministry of Science, Innovation and University, Madrid, Spain.; Department of Medicine, School of Medicine, University of Deusto, Bilbao, Spain., Pujol A; Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain.; Center for Biomedical Research on Rare Diseases, (CIBERER U759) Ministry of Science Innovation and University, Madrid, Spain.; Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain.
Jazyk: angličtina
Zdroj: Aging cell [Aging Cell] 2024 Oct 16, pp. e14355. Date of Electronic Publication: 2024 Oct 16.
DOI: 10.1111/acel.14355
Abstrakt: 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.
(© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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