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

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.

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Publication Details

Journal
Aging Cell
Published
2024-10-16
DOI
https://doi.org/10.1111/acel.14355
Citations
4
Primary Topic
Hereditary Neurological Disorders
Type
article
Field-Weighted Citation Impact
1.07

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article

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

María Marsal, Jon Ondaro, Agustí Rodríguez‐Palmero, Edgard Verdura et al.
4 citations
Aging Cell
Hereditary Neurological Disorders
1.07
article

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

María Marsal, Jon Ondaro, Agustí Rodríguez‐Palmero, Edgard Verdura, Montserrat Ruíz, Stéphane Fourcade, Pablo Loza‐Álvarez, Agatha Schlüter, Garazi Labayru, Pablo Iruzubieta, Nathalie Launay, Aurora Pujol, Andone Sistiaga, Miren Zulaica, Maria Espinosa‐Alcantud, Gorka Fernández‐Eulate, Alejandro Vaquero, Adolfo López de Munain
article en
4 citations

Abstract

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.

Aging CellVol. 24(1)
Institució Catalana de Recerca i Estudis Avançats (ES), Universitat Autònoma de Barcelona (ES), Universidad de Deusto (ES), University of the Basque Country (ES), Institute of Photonic Sciences (ES), Sorbonne Université (FR), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Institut d'Investigació Biomédica de Bellvitge (ES), Josep Carreras Leukaemia Research Institute (ES), Biogipuzkoa Health Research Institute (ES), Centre for Biomedical Network Research on Rare Diseases (ES), Institut de Myologie (FR), Pitié-Salpêtrière Hospital (FR), Duran i Reynals Hospital (ES), Hospital Universitari Germans Trias i Pujol (ES)
Ministerio de Economía y Competitividad, Instituto de Salud Carlos III
Openalex Percentile: Top 24%
Hereditary Neurological Disorders
1.07
DOIOpen Access PDFOpenAlex
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