Everolimus rescues multiple cellular defects in laminopathy-patient fibroblasts

Proc Natl Acad Sci U S A. 2018 Apr 17;115(16):4206-4211. doi: 10.1073/pnas.1802811115. Epub 2018 Mar 26.


LMNA encodes the A-type lamins that are part of the nuclear scaffold. Mutations in LMNA can cause a variety of disorders called laminopathies, including Hutchinson-Gilford progeria syndrome (HGPS), atypical Werner syndrome, and Emery-Dreifuss muscular dystrophy. Previous work has shown that treatment of HGPS cells with the mTOR inhibitor rapamycin or with the rapamycin analog everolimus corrects several of the phenotypes seen at the cellular level-at least in part by increasing autophagy and reducing the amount of progerin, the toxic form of lamin A that is overproduced in HGPS patients. Since other laminopathies also result in production of abnormal and potentially toxic lamin proteins, we hypothesized that everolimus would also be beneficial in those disorders. To test this, we applied everolimus to fibroblast cell lines from six laminopathy patients, each with a different mutation in LMNA Everolimus treatment increased proliferative ability and delayed senescence in all cell lines. In several cell lines, we observed that with treatment, there is a significant improvement in nuclear blebbing, which is a cellular hallmark of HGPS and other lamin disorders. These preclinical results suggest that everolimus might have clinical benefit for multiple laminopathy syndromes.

Keywords: everolimus; lamin; laminopathies; mTOR; progeria.

MeSH terms

  • Biomarkers
  • Cell Division / drug effects
  • Cell Line
  • Cell Nucleus / drug effects
  • Cell Nucleus / ultrastructure
  • Cellular Senescence / drug effects
  • Everolimus / pharmacology*
  • Fibroblasts / drug effects*
  • Humans
  • Lamin Type A / deficiency*
  • Lamin Type A / genetics
  • Muscular Dystrophy, Emery-Dreifuss / genetics*
  • Muscular Dystrophy, Emery-Dreifuss / pathology
  • Mutation
  • Phosphorylation / drug effects
  • Progeria / genetics*
  • Progeria / pathology
  • Protein Processing, Post-Translational / drug effects
  • Ribosomal Protein S6 / metabolism
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • Werner Syndrome / genetics*
  • Werner Syndrome / pathology


  • Biomarkers
  • LMNA protein, human
  • Lamin Type A
  • Ribosomal Protein S6
  • Everolimus
  • MTOR protein, human
  • TOR Serine-Threonine Kinases