Fragoso-Luna Adrián, Askjaer Peter
Andalusian Centre for Developmental Biology, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Pablo de Olavide, Sevilla, Spain.
Subcell Biochem. 2023;102:53-75. doi: 10.1007/978-3-031-21410-3_3.
Development from embryo to adult, organismal homeostasis and ageing are consecutive processes that rely on several functions of the nuclear envelope (NE). The NE compartmentalises the eukaryotic cells and provides physical stability to the genetic material in the nucleus. It provides spatiotemporal regulation of gene expression by controlling nuclear import and hence access of transcription factors to target genes as well as organisation of the genome into open and closed compartments. In addition, positioning of chromatin relative to the NE is important for DNA replication and repair and thereby also for genome stability. We discuss here the relevance of the NE in two classes of age-related human diseases. Firstly, we focus on the progeria syndromes Hutchinson-Gilford (HGPS) and Nestor-Guillermo (NGPS), which are caused by mutations in the LMNA and BANF1 genes, respectively. Both genes encode ubiquitously expressed components of the nuclear lamina that underlines the nuclear membranes. HGPS and NGPS patients manifest symptoms of accelerated ageing and cells from affected individuals show similar defects as cells from healthy old donors, including signs of increased DNA damage and epigenetic alternations. Secondly, we describe how several age-related neurodegenerative diseases, such as amyotrophic lateral sclerosis and Huntington's disease, are related with defects in nucleocytoplasmic transport. A common feature of this class of diseases is the accumulation of nuclear pore proteins and other transport factors in inclusions. Importantly, genetic manipulations of the nucleocytoplasmic transport machinery can alleviate disease-related phenotypes in cell and animal models, paving the way for potential therapeutic interventions.
从胚胎发育到成年，生物体的体内平衡和衰老过程是连续的，这些过程依赖于核膜（NE）的多种功能。核膜将真核细胞分隔开来，并为细胞核中的遗传物质提供物理稳定性。它通过控制核输入，从而控制转录因子对靶基因的接近以及将基因组组织成开放和封闭的区域，来提供基因表达的时空调节。此外，染色质相对于核膜的定位对于DNA复制和修复很重要，因此对基因组稳定性也很重要。我们在此讨论核膜在两类与年龄相关的人类疾病中的相关性。首先，我们关注早老综合征哈钦森 - 吉尔福德早衰症（HGPS）和内斯特 - 吉列尔莫早衰症（NGPS），它们分别由LMNA和BANF1基因的突变引起。这两个基因都编码普遍表达的核纤层蛋白成分，核纤层蛋白构成核膜的内层。HGPS和NGPS患者表现出加速衰老的症状，受影响个体的细胞表现出与健康老年供体的细胞类似的缺陷，包括DNA损伤增加和表观遗传改变的迹象。其次，我们描述了几种与年龄相关的神经退行性疾病，如肌萎缩侧索硬化症和亨廷顿病，是如何与核质运输缺陷相关的。这类疾病的一个共同特征是核孔蛋白和其他运输因子在包涵体中积累。重要的是，对核质运输机制的基因操作可以减轻细胞和动物模型中与疾病相关的表型，为潜在的治疗干预铺平道路。
