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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Distinct structural and mechanical properties of the nuclear lamina in Hutchinson-Gilford progeria syndrome
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Distinct structural and mechanical properties of the nuclear lamina in Hutchinson-Gilford progeria syndrome

机译：Hutchinson-Gilford早衰综合征的核层不同的结构和力学性质

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摘要

The nuclear lamina is a network of structural filaments, the A and B type lamins, located at the nuclear envelope and throughout the nucleus. Lamin filaments provide the nucleus with mechanical stability and support many basic activities, including gene regulation. Mutations in LMNA, the gene encoding A type lamins, cause numerous human diseases, including the segmental premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). Here we show that structural and mechanical properties of the lamina are altered in HGPS cells. We demonstrate by live-cell imaging and biochemical analysis that lamins A and C become trapped at the nuclear periphery in HGPS patient cells. Using micropipette aspiration, we show that the lamina in HGPS cells has a significantly reduced ability to rearrange under mechanical stress. Based on polarization microscopy results, we suggest that the lamins are disordered in the healthy nuclei, whereas the lamins in HGPS nuclei form orientationally ordered microdomains. The reduced deformability of the HGPS nuclear lamina possibly could be due to the inability of these orientationally ordered microdomains to dissipate mechanical stress. Surprisingly, intact HGPS cells exhibited a degree of resistance to acute mechanical stress similar to that of cells from healthy individuals. Thus, in contrast to the nuclear fragility seen in Imna null cells, the lamina network in HGPS cells has unique mechanical properties that might contribute to disease phenotypes by affecting responses to mechanical force and misregulation of mechanosensitive gene expression.
机译：核层是位于核膜和整个核内的结构细丝（A和B型层）的网络。薄层细丝为细胞核提供了机械稳定性，并支持许多基本活动，包括基因调控。 LMNA（一种编码A型lamins的基因）中的突变会引起多种人类疾病，包括部分过早衰老的Hutchinson-Gilford早衰综合症（HGPS）。在这里，我们显示了在HGPS单元中，层板的结构和机械性能发生了变化。我们通过活细胞成像和生化分析证明，lamin A和C被困在HGPS患者细胞的核外围。使用微量移液器抽吸，我们显示HGPS细胞中的层板在机械应力下具有明显降低的重排能力。基于极化显微镜的结果，我们认为健康的细胞核中的纤层蛋白是无序的，而HGPS细胞核中的纤层蛋白形成了取向有序的微区。 HGPS核层的可变形性降低可能是由于这些定向有序微区无法消除机械应力。令人惊讶的是，完整的HGPS细胞对急性机械应力的抵抗力与健康个体的细胞相似。因此，与在Imna null细胞中看到的核脆弱性相反，HGPS细胞中的椎板网络具有独特的机械特性，可能会通过影响对机械力的响应和机械敏感基因表达的失调来促进疾病表型。

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