Assessing the efficacy of protein farnesyltransferase inhibitors in mouse models of progeria

J Lipid Res. 2010 Feb;51(2):400-5. doi: 10.1194/jlr.M002808. Epub 2009 Oct 26.


Hutchinson-Gilford progeria syndrome (HGPS) is caused by the accumulation of a farnesylated form of prelamin A (progerin). Previously, we showed that blocking protein farnesylation with a farnesyltransferase inhibitor (FTI) ameliorates the disease phenotypes in mouse model of HGPS (Lmna(HG/+)). However, the interpretation of the FTI treatment studies is open to question in light of recent studies showing that mice expressing a nonfarnesylated version of progerin (Lmna(nHG/+)) develop progeria-like disease phenotypes. The fact that Lmna(nHG/+) mice manifest disease raised the possibility that the beneficial effects of an FTI in Lmna(HG/+) mice were not due to the effects of the drug on the farnesylation of progerin, but may have been due to unanticipated secondary effects of the drug on other farnesylated proteins. To address this issue, we compared the ability of an FTI to improve progeria-like disease phenotypes in both Lmna(HG/+) and Lmna(nHG/+) mice. In Lmna(HG/+) mice, the FTI reduced disease phenotypes in a highly significant manner, but the drug had no effect in Lmna(nHG/+) mice. The failure of the FTI to ameliorate disease in Lmna(nHG/+) mice supports the idea that the beneficial effects of an FTI in Lmna(HG/+) mice are due to the effect of drug on the farnesylation of progerin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism
  • Animals
  • Body Weight / drug effects
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Farnesyltranstransferase / antagonists & inhibitors*
  • Farnesyltranstransferase / metabolism
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use
  • Male
  • Mice
  • Phenotype
  • Prenylation / drug effects
  • Progeria / drug therapy*
  • Progeria / enzymology*
  • Progeria / metabolism
  • Progeria / pathology
  • Survival Analysis
  • Time Factors


  • ABT-100
  • Enzyme Inhibitors
  • Imidazoles
  • Farnesyltranstransferase