Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-8004, USA.
Sci Transl Med. 2011 Jun 29;3(89):89ra58. doi: 10.1126/scitranslmed.3002346.
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.
亨廷顿舞蹈病-吉福德早衰综合征（Hutchinson-Gilford progeria syndrome，HGPS）是一种致命的遗传性疾病，其特征为早衰。HGPS 最常见的病因是 lamin A/C 基因（LMNA）中的一个新生单核苷酸取代，该取代部分激活了外显子 11 中的一个隐蔽剪接供体位点，产生一种称为 progerin 的异常 lamin A 蛋白。在有丝分裂细胞中 progerin 的积累会对核支架的完整性产生不利影响，并导致培养细胞的核泡化。progerin 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（rapamycin）的作用，雷帕霉素是一种被认为能减缓细胞和机体衰老的大环内酯类抗生素，对 HGPS 成纤维细胞的细胞表型的影响。雷帕霉素处理可消除核泡化，延迟细胞衰老的发生，并增强 HGPS 细胞中 progerin 的降解。雷帕霉素还减少了不溶性 progerin 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。我们的发现为雷帕霉素对长寿的有益作用提供了另一种机制，并鼓励假设雷帕霉素治疗可能为 HGPS 患儿提供临床益处。
