Assessing the efficacy 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

doi:10.1194/jlr.m002808

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 (LmnaHG/+). 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 (LmnanHG/+) develop progeria-like disease phenotypes. The fact that LmnanHG/+ mice manifest disease raised the possibility that the beneficial effects of an FTI in LmnaHG/+ 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 LmnaHG/+ and LmnanHG/+ mice. In LmnaHG/+ mice, the FTI reduced disease phenotypes in a highly significant manner, but the drug had no effect in LmnanHG/+ mice. The failure of the FTI to ameliorate disease in LmnanHG/+ mice supports the idea that the beneficial effects of an FTI in LmnaHG/+ mice are due to the effect of drug on the farnesylation of progerin.

Highlights

Hutchinson-Gilford progeria syndrome (HGPS) is caused by the accumulation of a farnesylated form of prelamin A
Our goal was to determine if the farnesyltransferase inhibitor (FTI) would ameliorate progeria-like disease phenotypes in LmnanHG/+ mice in addition to LmnaHG/+ mice
When we incubated LmnaHG/+ and LmnanHG/+ fibroblasts with the same concentration of ABT-100 that we achieved in mice (0.5 ␮g/ml), the farnesylation of B-type lamins and progerin was inhibited, as judged by metabolic labeling experiments with a farnesol analog (8-anilinogeraniol) (Fig. 1)

Summary

Introduction

Hutchinson-Gilford progeria syndrome (HGPS) is caused by the accumulation of a farnesylated form of prelamin A (progerin). We showed that blocking protein farnesylation with a farnesyltransferase inhibitor (FTI) ameliorates the disease phenotypes in mouse model of HGPS (LmnaHG/+). The fact that LmnanHG/+ mice manifest disease raised the possibility that the beneficial effects of an FTI in LmnaHG/+ 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 LmnaHG/+ and LmnanHG/+ mice.

Objectives

Methods

Results

Conclusion