title: Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells.
abstract: 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.
authors.affiliation: Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-8004, USA.
authors.forename: Kan
authors.initials: K
authors.lastname: Cao
authors.forename: John J
authors.initials: JJ
authors.lastname: Graziotto
authors.forename: Cecilia D
authors.initials: CD
authors.lastname: Blair
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Mazzulli
authors.forename: Michael R
authors.initials: MR
authors.lastname: Erdos
authors.forename: Dimitri
authors.initials: D
authors.lastname: Krainc
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011371:Progeria / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; D011993:Recombinant Fusion Proteins; C090764:prelamin A; D020123:Sirolimus