Buchwalter Abigail, Hetzer Martin W
Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA.
Nat Commun. 2017 Aug 30;8(1):328. doi: 10.1038/s41467-017-00322-z.
Premature aging disorders provide an opportunity to study the mechanisms that drive aging. In Hutchinson-Gilford progeria syndrome (HGPS), a mutant form of the nuclear scaffold protein lamin A distorts nuclei and sequesters nuclear proteins. We sought to investigate protein homeostasis in this disease. Here, we report a widespread increase in protein turnover in HGPS-derived cells compared to normal cells. We determine that global protein synthesis is elevated as a consequence of activated nucleoli and enhanced ribosome biogenesis in HGPS-derived fibroblasts. Depleting normal lamin A or inducing mutant lamin A expression are each sufficient to drive nucleolar expansion. We further show that nucleolar size correlates with donor age in primary fibroblasts derived from healthy individuals and that ribosomal RNA production increases with age, indicating that nucleolar size and activity can serve as aging biomarkers. While limiting ribosome biogenesis extends lifespan in several systems, we show that increased ribosome biogenesis and activity are a hallmark of premature aging.HGPS is a premature aging disease caused by mutations in the nuclear protein lamin A. Here, the authors show that cells from patients with HGPS have expanded nucleoli and increased protein synthesis, and report that nucleoli also expand as aging progresses in cells derived from healthy individuals.
早衰性疾病为研究驱动衰老的机制提供了契机。在哈钦森 - 吉尔福德早衰综合征（HGPS）中，核支架蛋白核纤层蛋白A的一种突变形式会使细胞核变形并隔离核蛋白。我们试图研究这种疾病中的蛋白质稳态。在此，我们报告与正常细胞相比，源自HGPS的细胞中蛋白质周转率普遍增加。我们确定，由于源自HGPS的成纤维细胞中核仁活化和核糖体生物合成增强，整体蛋白质合成增加。耗尽正常核纤层蛋白A或诱导突变型核纤层蛋白A表达均足以驱动核仁扩张。我们进一步表明，在源自健康个体的原代成纤维细胞中，核仁大小与供体年龄相关，并且核糖体RNA产生随年龄增加，这表明核仁大小和活性可作为衰老生物标志物。虽然限制核糖体生物合成在多个系统中可延长寿命，但我们表明核糖体生物合成和活性增加是早衰的一个标志。HGPS是一种由核蛋白核纤层蛋白A突变引起的早衰性疾病。在此，作者表明来自HGPS患者的细胞具有扩大的核仁且蛋白质合成增加，并报告在源自健康个体的细胞中，随着衰老进展核仁也会扩大。
