Rapamycin Reverses Cellular Phenotypes and Enhances Mutant Protein Clearance in Hutchinson-Gilford Progeria Syndrome Cells

@article{Cao2011RapamycinRC,
  title={Rapamycin Reverses Cellular Phenotypes and Enhances Mutant Protein Clearance in Hutchinson-Gilford Progeria Syndrome Cells},
  author={Kan Cao and John J. Graziotto and Cecilia D Blair and Joseph R. Mazzulli and Michael R. Erdos and Dimitri Krainc and Francis S. Collins},
  journal={Science Translational Medicine},
  year={2011},
  volume={3},
  pages={89ra58 - 89ra58}
}
Shown previously to extend longevity in animals, the drug rapamycin might serve as a treatment for a human premature aging syndrome. The Young and the Youthless In the novel Brideshead Revisited, Evelyn Waugh reminisces about “the langor of youth” and laments “how quickly, how irrecoverably lost” is the bloom. Although every adult can relate to this cri de coeur, in no case is youth lost more swiftly or more dramatically than in children suffering from Hutchinson-Gilford progeria syndrome (HGPS… Expand
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TLDR
It is found that the causative aberrant protein, progerin, was cleared through autophagic mechanisms when the cells were treated with rapamycin, suggesting a new potential treatment for HGPS and normal aging. Expand
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TLDR
It is demonstrated that an already developed HGPS bone disease phenotype to a large extent could be reversed in a mouse model, and the results suggest that mesenchymal stem cell transplantation from healthy donors might be a treatment strategy for HGPS that could be tested in this mouse model. Expand
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Hutchinson‐Gilford progeria syndrome (HGPS) is a rare accelerated aging disorder most notably characterized by cardiovascular disease and premature death from myocardial infarction or stroke. TheExpand
Temsirolimus Partially Rescues the Hutchinson-Gilford Progeria Cellular Phenotype
TLDR
Tests on rapamycin’s efficacy with regard to proteostasis, mitochondrial function and the degree of DNA damage suggest that future therapeutic strategies should identify new drug combinations and treatment regimens that target all the dysfunctional hallmarks that characterize HGPS cells. Expand
Neuropeptide Y Enhances Progerin Clearance and Ameliorates the Senescent Phenotype of Human Hutchinson-Gilford Progeria Syndrome Cells
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NPY increases autophagic flux and progerin clearance in primary cultures of human dermal fibroblasts from HGPS patients, and rescues several hallmarks of cellular aging in HGPS cells, suggesting that NPY can be considered a promising strategy to delay or block the premature aging of HGPS. Expand
HUTCHINSON-GILFORD PROGERIA SYNDROME: A PREMATURELY AGING DISORDER
TLDR
The clinical characteristics of this disease, the underlying mutation in the lamin A (LMNA) gene that results in this phenotype and the recent advances in treatment strategies are summarized. Expand
Investigation into the human premature ageing disease, Hutchinson Gilford Progeria syndrome, using hTERT immortalised fibroblasts
TLDR
The characterisation of an hTERT immortalised cell line led to the observation of a genetic instability phenotype, which has enabled the identification of candidate genes within DNA repair and cell cycle regulation, and the development of TATlamin A and TATprogerin fusion proteins, which are capable of transducing into human cells at a desired concentration, allow for future investigation into progerin dose effects. Expand
Sulforaphane enhances progerin clearance in Hutchinson–Gilford progeria fibroblasts
TLDR
Progerin induces changes in the composition of the HGPS nuclear proteome, including alterations to several components of the protein degradation pathways, and sulforaphane (SFN), an antioxidant derived from cruciferous vegetables, stimulates proteasome activity and autophagy in normal and HGPS fibroblast cultures and reverses the phenotypic changes that are the hallmarks of HGPS. Expand
Inhibition of JAK-STAT Signaling with Baricitinib Reduces Inflammation and Improves Cellular Homeostasis in Progeria Cells
TLDR
Ex vivo data using human cell models indicate that the overactivation of JAK-STAT signaling mediates premature senescence and that the inhibition of this pathway could show promise for the treatment of HGPS and age-related pathologies. Expand
Identification of mitochondrial dysfunction in Hutchinson-Gilford progeria syndrome through use of stable isotope labeling with amino acids in cell culture.
TLDR
expression and functional studies confirmed that mitochondrial dysfunction is a feature of progeria which develops in a time- and dose-dependent manner and improved mitochondrial function is demonstrated in progeroid mouse cells treated with a combination of statins and aminobisphosphonates, two drugs that are being evaluated in ongoing HGPS clinical trials. Expand
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