ABSTRACT The nuclear lamina is a meshwork of intermediate filament proteins, and lamin A is the primary mechanical protein. An altered splicing of lamin A, known as progerin, causes the disease Hutchinson-Gilford progeria syndrome. Progerin-expressing cells have altered nuclear shapes and stiffened nuclear lamina with microaggregates of progerin. Here, progerin microaggregate inclusions in the lamina are shown to lead to cellular and multicellular dysfunction. We show with Comsol simulations that stiffened inclusions causes redistribution of normally homogeneous forces, and this redistribution is dependent on the stiffness difference and relatively independent of inclusion size. We also show mechanotransmission changes associated with progerin expression in cells under confinement and cells under external forces. Endothelial cells expressing progerin do not align properly with patterning. Fibroblasts expressing progerin do not align properly to applied cyclic force. Combined, these studies show that altered nuclear lamina mechanics and microstructure impacts cytoskeletal force transmission through the cell.

中文翻译：

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Lamin 微聚集体导致表达早老蛋白的细胞中的机械传递改变

摘要 核纤层是中间丝蛋白的网状结构，核纤层蛋白 A 是主要的机械蛋白。被称为早衰蛋白的 lamin A 的改变剪接导致疾病哈钦森-吉尔福德早衰综合征。Progerin 表达细胞的细胞核形状发生了改变，并且具有 progerin 微聚集体的核层变硬。在这里，叶片中的早老素微聚集体被证明会导致细胞和多细胞功能障碍。我们通过 Comsol 模拟表明，硬化的夹杂物会导致正常均匀力的重新分布，这种重新分布取决于刚度差异，并且相对独立于夹杂物尺寸。我们还显示了与限制条件下的细胞和外力下的细胞中早衰蛋白表达相关的机械传递变化。表达早老素的内皮细胞与图案不正确对齐。表达早老素的成纤维细胞与施加的循环力不正确对齐。综合起来，这些研究表明改变的核层力学和微观结构会影响细胞骨架力通过细胞的传递。