Assessing the effi cacy of protein farnesyltransferase inhibitors in mouse models of progeria

Shao H. Yang, Sandy Y. Chang, Douglas A. Andres, H. Peter Spielmann, Stephen G. Young, Loren G. Fong

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

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 benefi cial 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 benefi cial effects of an FTI in Lmna HG/+ mice are due to the effect of drug on the farnesylation of progerin.-Yang, S. H., S. Y. Chang, D. A. Andres, H. P. Spielmann, S. G. Young, and L. G. Fong. Assessing the effi cacy of protein farnesyltransferase inhibitors in mouse models of progeria.

Original languageEnglish
Pages (from-to)400-405
Number of pages6
JournalJournal of Lipid Research
Volume51
Issue number2
DOIs
StatePublished - Feb 1 2010

Keywords

  • Aging
  • Farnesylation
  • Knock in mice
  • Lamin A
  • Posttranslational modifi cations
  • Protein farnesyltransferase
  • Protein prenylation

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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