SVBP 功能失常导致的微管蛋白去酪氨酸化改变诱导细胞分裂失败和衰老,是复杂的遗传性痉挛性截瘫的基础。

IF 8 1区 医学 Q1 CELL BIOLOGY
Aging Cell Pub Date : 2024-10-16 DOI:10.1111/acel.14355
Nathalie Launay, Maria Espinosa-Alcantud, Edgard Verdura, Gorka Fernández-Eulate, Jon Ondaro, Pablo Iruzubieta, Maria Marsal, Agatha Schlüter, Montserrat Ruiz, Stephane Fourcade, Agustí Rodríguez-Palmero, Miren Zulaica, Andone Sistiaga, Garazi Labayru, Pablo Loza-Alvarez, Alejandro Vaquero, Adolfo Lopez de Munain, Aurora Pujol
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引用次数: 0

摘要

以永久性细胞周期停滞为标志的衰老可能会导致再生潜能和神经元功能下降,从而诱发神经退行性疾病。在这项研究中,我们采用全外显子组测序技术,在来自三个无血缘关系家庭的六名患者中鉴定出了一种之前未报道过的 SVBP 双倍拷贝错义变体(p.Leu49Pro)。这些患者表现为复杂的遗传性痉挛性截瘫(HSP)、周围神经病变、语言障碍和智力障碍,与之前描述的SVBP无义突变患者相比,表现型较轻。与 SVBP 作为 VASH 介导的微管蛋白去酪氨酸化所必需的伴侣蛋白的主要作用相一致,p.Leu49Pro 突变的患者成纤维细胞和 SVBP 基因敲除的 HeLa 细胞都表现出微管动态不稳定性以及包膜物质(PCM)成分贩运和中心体内聚力的改变。在患者成纤维细胞中,中心体的结构异常会引发有丝分裂错误和细胞衰老。值得注意的是,在患者外周血单核细胞(PBMC)中也观察到了以 p16INK4 水平升高为特征的早衰。总之,我们的研究结果强调了 SVBP 在中枢神经系统发育和维持过程中的关键作用,为细胞分裂失败与大脑皮层运动神经元疾病和智力障碍之间的联系提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Altered tubulin detyrosination due to SVBP 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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来源期刊
Aging Cell
Aging Cell Biochemistry, Genetics and Molecular Biology-Cell Biology
自引率
2.60%
发文量
212
期刊介绍: Aging Cell is an Open Access journal that focuses on the core aspects of the biology of aging, encompassing the entire spectrum of geroscience. The journal's content is dedicated to publishing research that uncovers the mechanisms behind the aging process and explores the connections between aging and various age-related diseases. This journal aims to provide a comprehensive understanding of the biological underpinnings of aging and its implications for human health. The journal is widely recognized and its content is abstracted and indexed by numerous databases and services, which facilitates its accessibility and impact in the scientific community. These include: Academic Search (EBSCO Publishing) Academic Search Alumni Edition (EBSCO Publishing) Academic Search Premier (EBSCO Publishing) Biological Science Database (ProQuest) CAS: Chemical Abstracts Service (ACS) Embase (Elsevier) InfoTrac (GALE Cengage) Ingenta Select ISI Alerting Services Journal Citation Reports/Science Edition (Clarivate Analytics) MEDLINE/PubMed (NLM) Natural Science Collection (ProQuest) PubMed Dietary Supplement Subset (NLM) Science Citation Index Expanded (Clarivate Analytics) SciTech Premium Collection (ProQuest) Web of Science (Clarivate Analytics) Being indexed in these databases ensures that the research published in Aging Cell is discoverable by researchers, clinicians, and other professionals interested in the field of aging and its associated health issues. This broad coverage helps to disseminate the journal's findings and contributes to the advancement of knowledge in geroscience.
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