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首页> 外文期刊>European Journal of Histochemistry >Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria
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Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria

机译：自噬降解法呢基前醇溶蛋白A作为治疗椎板连接早衰的方法

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摘要

Farnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to chromatin damage and cellular senescence and ultimately causes skin and endothelial defects, bone resorption, lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying prelamin A turnover is critical for the development of clinically effective protein inhibitors that can avoid accumulation to toxic levels without impairing lamin A/C expression, which is essential for normal biological functions. Little is known about specific molecules that may target farnesylated prelamin A to elicit protein degradation. Here, we report the discovery of rapamycin as a novel inhibitor of progerin, which dramatically and selectively decreases protein levels through a mechanism involving autophagic degradation. Rapamycin treatment of progeria cells lowers progerin, as well as wild-type prelamin A levels, and rescues the chromatin phenotype of cultured fibroblasts including histone methylation status and BAF and LAP2α distribution patterns. Importantly, rapamycin treatment does not affect lamin C protein levels, but increases the relative expression of the prelamin A endoprotease ZMPSTE24. Thus, rapamycin, an antibiotic belonging to the class of macrolides, previously found to increase longevity in mouse models, can serve as a therapeutic tool, to eliminate progerin, avoid farnesylated prelamin A accumulation, and restore chromatin dynamics in progeroid laminopathies.
机译：法尼基化的前醇溶蛋白A是在层粘蛋白A的成熟途径中产生的加工中间体。截短的法尼基化的醇溶蛋白A形式（称为早老蛋白）的积累是严重早衰综合症Hutchinson-Gilford早衰的标志。早春素在细胞中引起毒性作用，导致染色质受损和细胞衰老，并最终引起皮肤和内皮缺陷，骨吸收，脂肪营养不良和加速衰老。对prelamin A转换的潜在机制的了解对于开发临床有效的蛋白抑制剂至关重要，该蛋白抑制剂可避免积累至毒性水平而不损害lamin A / C表达，而lamin A / C表达对于正常的生物学功能至关重要。对于可能靶向法尼基化的醇溶蛋白A引起蛋白质降解的特定分子知之甚少。在这里，我们报告了雷帕霉素作为早老蛋白的新型抑制剂的发现，它通过涉及自噬降解的机制显着选择性地降低了蛋白质水平。雷帕霉素对早老细胞的治疗降低了早老蛋白以及野生型prelamin A的水平，并拯救了培养的成纤维细胞的染色质表型，包括组蛋白甲基化状态以及BAF和LAP2α分布模式。重要的是，雷帕霉素处理不会影响层粘连蛋白C的蛋白水平，但会增加prelamin A内切蛋白酶ZMPSTE24的相对表达。因此，雷帕霉素（一种属于大环内酯类的抗生素，以前发现可延长小鼠模型的寿命）可作为一种治疗工具，消除早老素，避免法尼基化的前纤溶蛋白A蓄积并恢复早衰型拉丁病患者的染色质动力学。

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