Rapamycin Reverses Cellular Phenotypes and Enhances Mutant Protein Clearance in Hutchinson-Gilford Progeria Syndrome Cells
Rapamycin Reverses Cellular Phenotypes and Enhances Mutant Protein Clearance in Hutchinson-Gilford Progeria Syndrome Cells
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DOI：
10.1126/scitranslmed.3002346
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发表时间：
2011-06-29
影响因子：
17.1
通讯作者：
Collins, Francis S.
中科院分区：
文献类型：
--
作者：
Cao, Kan;Graziotto, John J.;Collins, Francis S.
Hutchinson-Gilford早衰综合征（HGPS）是一种以过早衰老为特征的致死性遗传疾病。HGPS最常见的是由核纤层蛋白A/C基因（LMNA）中的从头单核苷酸取代引起的，该取代部分激活外显子11中的隐蔽剪接供体位点，产生称为早老蛋白的异常核纤层蛋白A蛋白。早老蛋白在分裂细胞中的积累对核支架的完整性产生不利影响，并导致培养细胞中的核起泡。早老蛋白也在正常细胞中产生，随着衰老的临近而增加。在这里，我们报告了雷帕霉素，一种大环内酯类抗生素，已被牵连在减缓细胞和有机体衰老，对HGPS成纤维细胞的细胞表型的影响。用雷帕霉素处理废除核起泡，延迟细胞衰老的开始，并增强HGPS细胞中早老蛋白的降解。雷帕霉素还减少了不溶性早老蛋白聚集体的形成，并通过正常成纤维细胞中的自噬机制诱导清除。我们的研究结果提示了雷帕霉素对长寿有益作用的另一种机制，并鼓励雷帕霉素治疗可为HGPS儿童提供临床益处的假设。
Hutchinson-Gilford progeria syndrome (HGPS) is a lethal genetic disorder characterized by premature aging. HGPS is most commonly caused by a de novo single-nucleotide substitution in the lamin A/C gene (LMNA) that partially activates a cryptic splice donor site in exon 11, producing an abnormal lamin A protein termed progerin. Accumulation of progerin in dividing cells adversely affects the integrity of the nuclear scaffold and leads to nuclear blebbing in cultured cells. Progerin is also produced in normal cells, increasing in abundance as senescence approaches. Here, we report the effect of rapamycin, a macrolide antibiotic that has been implicated in slowing cellular and organismal aging, on the cellular phenotypes of HGPS fibroblasts. Treatment with rapamycin abolished nuclear blebbing, delayed the onset of cellular senescence, and enhanced the degradation of progerin in HGPS cells. Rapamycin also decreased the formation of insoluble progerin aggregates and induced clearance through autophagic mechanisms in normal fibroblasts. Our findings suggest an additional mechanism for the beneficial effects of rapamycin on longevity and encourage the hypothesis that rapamycin treatment could provide clinical benefit for children with HGPS.