Treatment with a farnesyltransferase inhibitor improves survival in mice with a Hutchinson-Gilford progeria syndrome mutation - PubMed (original) (raw)

Treatment with a farnesyltransferase inhibitor improves survival in mice with a Hutchinson-Gilford progeria syndrome mutation

Shao H Yang et al. Biochim Biophys Acta. 2008 Jan-Feb.

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a progeroid syndrome characterized by multiple aging-like disease phenotypes. We recently reported that a protein farnesyltransferase inhibitor (FTI) improved several disease phenotypes in mice with a HGPS mutation (Lmna(HG/+)). Here, we investigated the impact of an FTI on the survival of Lmna(HG/+) mice. The FTI significantly improved the survival of both male and female Lmna(HG/+) mice. Treatment with the FTI also improved body weight curves and reduced the number of spontaneous rib fractures. This study provides further evidence for a beneficial effect of an FTI in HGPS.

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Figures

Fig. 1

Fig. 1

Western blot analysis of liver extracts. FTI treatment of Lmna+/+ mice leads to the appearance of nonfarnesylated HDJ-2 (with an antibody against HDJ-2) in liver extracts. FTI treatment also leads to the appearance of nonfarnesylated prelamin A (as judged by a western blot with a prelamin A–specific antibody). However, the amount of prelamin A accumulation was small, as judged by a western blot with an antibody against lamin A/C (prelamin A is a faint shadow above a large lamin A band). The FTI did not reduce the levels of mature lamin A.

Fig. 2

Fig. 2

Kaplan-Meier survival plots for _Lmna_HG/+ mice treated with an FTI or vehicle alone. Male _Lmna_HG/+ mice on vehicle (n = 8); male _Lmna_HG/+ mice on FTI (n = 10); female _Lmna_HG/+ mice on vehicle (n = 8); female _Lmna_HG/+ mice on FTI (n = 13).

Fig. 3

Fig. 3

Disease phenotypes in _Lmna_HG/+ mice with FTI treatment. (a and b) Body weight curves for male (a) and female (b) _Lmna_HG/+ and littermate Lmna+/+ mice treated with an FTI or vehicle alone, beginning at four weeks of age. The body weight curves for FTI-treated _Lmna_HG/+ mice were significantly different than those of the vehicle-treated _Lmna_HG/+ mice, both in males and in females (P < 0.0001, as judged by the repeated-measure analysis of variance method). (c) Spontaneous rib fractures in male (squares) and female (circles) FTI- and vehicle-treated _Lmna_HG/+ mice at the time that they died. The FTI-treated mice had fewer fractures (P < 0.0001 for both males and females).

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