Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells

Kan Cao, John J. Graziotto, Cecilia D. Blair, Joseph R. Mazzulli, Michael R. Erdos, Dimitri Krainc*, Francis S. Collins

*Corresponding author for this work

Research output: Contribution to journalArticle

200 Citations (Scopus)

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.

Original languageEnglish (US)
Article number89ra58
JournalScience translational medicine
Volume3
Issue number89
DOIs
StatePublished - Jun 29 2011

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Progeria
Mutant Proteins
Sirolimus
Phenotype
Lamin Type A
RNA Splice Sites
Cell Aging
Blister
Fibroblasts
Premature Aging
Nuclear Matrix
Inborn Genetic Diseases
Macrolides
Exons
Cultured Cells
Nucleotides
Anti-Bacterial Agents
Therapeutics
Genes
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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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.",
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Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells. / Cao, Kan; Graziotto, John J.; Blair, Cecilia D.; Mazzulli, Joseph R.; Erdos, Michael R.; Krainc, Dimitri; Collins, Francis S.

In: Science translational medicine, Vol. 3, No. 89, 89ra58, 29.06.2011.

Research output: Contribution to journalArticle

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AU - Erdos, Michael R.

AU - Krainc, Dimitri

AU - Collins, Francis S.

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