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The contrasting roles of lamin B1 in cellular aging and human disease

机译:Lamin B1在细胞衰老和人类疾病中的对比作用

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The nuclear lamina underlies the inner nuclear membrane and consists of a proteinaceous meshwork of intermediate filaments: the A- and B-type lamins. Mutations in LMNA (encoding lamin A and C) give rise to a variety of human diseases including muscular dystrophies, cardiomyopathies and the premature aging syndrome progeria (HGPS). Duplication of the LMNB1 locus, leading to elevated levels of lamin B1, causes adult-onset autosomal dominant leukodystrophy (ADLD), a rare genetic disease that leads to demyelination in the central nervous system (CNS). Conversely, reduced levels of lamin B1 have been observed in HGPS patient derived fibroblasts, as well as fibroblasts and keratinocytes undergoing replicative senescence, suggesting that the regulation of lamin B1 is important for cellular physiology and disease. However, the causal relationship between low levels of lamin B1 and cellular senescence and its relevance in vivo remain unclear. How do elevated levels of lamin B1 cause disease and why is the CNS particularly susceptible to lamin B1 fluctuations? Here we summarize recent findings as to how perturbations of lamin B1 affect cellular physiology and discuss the implications this has on senescence, HGPS and ADLD.
机译:核层位于内核膜之下,由中间细丝的蛋白质网状结构组成:A型和B型层。 LMNA(编码层蛋白A和C)的突变会引起多种人类疾病,包括肌肉营养不良,心肌病和早衰综合症早衰症(HGPS)。 LMNB1基因座重复,导致层粘连蛋白B1水平升高,导致成人发作的常染色体显性遗传性白细胞营养不良(ADLD),这是一种罕见的遗传疾病,可导致中枢神经系统(CNS)脱髓鞘。相反,在HGPS患者衍生的成纤维细胞以及经历复制性衰老的成纤维细胞和角质形成细胞中,观察到层粘连蛋白B1的水平降低,这表明层粘连蛋白B1的调节对于细胞生理和疾病很重要。然而,低水平的lamin B1与细胞衰老之间的因果关系及其在体内的相关性仍不清楚。升高的Lamin B1水平如何引起疾病,为什么CNS特别容易受到Lamin B1波动的影响?在这里,我们概述了有关层粘连蛋白B1的扰动如何影响细胞生理的最新发现,并讨论了其对衰老,HGPS和ADLD的影响。

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