Cited by 350Nuclear Structure and FunctionGenetics, Aging, and Longevity in Model OrganismsTelomeres, Telomerase, and Senescence

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.·2011·Science Translational Medicine

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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Crossref · 10.1126/scitranslmed.3002346

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Authors
Cao, K., Graziotto, J. J., Blair, C. D., Mazzulli, J. R., Erdos, M. R., Krainc, D., & Collins, F. S.
Affiliations
  • National Institutes of Health (US)
  • Harvard University (US)
Corresponding author
  • Cao, Kan
  • Graziotto, John J.
  • Krainc, Dimitri
  • Collins, Francis S.
Venue
Science Translational Medicine
Published
2011-06-29
Volume
3
Issue
89
Pages
89ra58-89ra58
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
OpenAlex
W2166403801
Cited by
350
References
38
Citations by year
2026: 6 · 2025: 12 · 2024: 15 · 2023: 13 · 2022: 19 · 2021: 20 · 2020: 25 · 2019: 20 · 2018: 34 · 2017: 23 · 2016: 31 · 2015: 22 · 2014: 25 · 2013: 36 · 2012: 32
FWCI
14.27
Type
journal article
Language
en
Open access
closed
Locations
  • Science Translational Medicine (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (R00AG029761)
  • National Institute of Neurological Disorders and Stroke (R01NS051303)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Keywords
Hutchinson-Gilford progeria syndrome, rapamycin, progerin, lamin A/C, cellular senescence, nuclear blebbing, autophagy, protein clearance, premature aging, fibroblasts, drug repurposing
MeSH terms
Animals, Antibiotics, Antineoplastic, Autophagy, Cell Nucleus, Cells, Cultured, Fibroblasts, HeLa Cells, Humans, Nuclear Proteins, Phenotype, Progeria, Protein Precursors, Recombinant Fusion Proteins, Sirolimus, Lamin Type A

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