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

Yang SH, Chang SY, Andres DA, Spielmann HP, Young SG, Fong LG - J. Lipid Res. (2009)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA.

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 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.

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Treatment with an FTI lowers steady-state levels of mature lamin A. A: Western blots of liver extracts from Lmna+/+, LmnaHG/+, and LmnanHG/+ mice that had been treated with a protein farnesyltransferase inhibitor (FTI) or vehicle (Veh) alone. Western blots were performed with antibodies against lamin A/C and prelamin A. Lmna+/+ fibroblasts, treated with either the FTI or the vehicle, were used as controls. Western blots were also performed with antibodies against HDJ-2, another farnesylated protein. Actin was used as a loading control. B: Quantification of lamin A levels in liver extracts of Lmna+/+, LmnaHG/+, and LmnanHG/+ mice (n = 3 mice/group; each sample was analyzed on two independent Western blots). Lamin A/actin ratios in liver extracts of FTI-treated mice were expressed relative to those in vehicle-treated mice. In the livers of Lmna+/+, LmnaHG/+, and LmnanHG/+ mice, the lamin A/actin ratio in FTI-treated mice was lower than in vehicle-treated mice (P < 0.0001). Error bars indicate SEM.
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fig2: Treatment with an FTI lowers steady-state levels of mature lamin A. A: Western blots of liver extracts from Lmna+/+, LmnaHG/+, and LmnanHG/+ mice that had been treated with a protein farnesyltransferase inhibitor (FTI) or vehicle (Veh) alone. Western blots were performed with antibodies against lamin A/C and prelamin A. Lmna+/+ fibroblasts, treated with either the FTI or the vehicle, were used as controls. Western blots were also performed with antibodies against HDJ-2, another farnesylated protein. Actin was used as a loading control. B: Quantification of lamin A levels in liver extracts of Lmna+/+, LmnaHG/+, and LmnanHG/+ mice (n = 3 mice/group; each sample was analyzed on two independent Western blots). Lamin A/actin ratios in liver extracts of FTI-treated mice were expressed relative to those in vehicle-treated mice. In the livers of Lmna+/+, LmnaHG/+, and LmnanHG/+ mice, the lamin A/actin ratio in FTI-treated mice was lower than in vehicle-treated mice (P < 0.0001). Error bars indicate SEM.

Mentions: The plasma levels of ABT-100 in treated mice were similar to those in earlier studies (12–14), ranging from 0.3 to 0.7 μg/ml. When we incubated LmnaHG/+ and LmnanHG/+ fibroblasts with the same concentration of ABT-100 that we achieved in mice (0.5 μg/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). Also, we observed, as expected, an accumulation of prelamin A and nonfarnesylated HDJ-2 in liver extracts from FTI-treated mice (Fig. 2A). Interestingly, there were lower levels of mature lamin A, relative to actin, in liver extracts from FTI-treated mice (Fig. 2A). Long-term treatment of LmnaHG/+ and LmnanHG/+ fibroblasts with ABT-100 also lowered levels of mature lamin A, consistent with the findings in FTI-treated mice (Fig. 3).


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

Yang SH, Chang SY, Andres DA, Spielmann HP, Young SG, Fong LG - J. Lipid Res. (2009)

Treatment with an FTI lowers steady-state levels of mature lamin A. A: Western blots of liver extracts from Lmna+/+, LmnaHG/+, and LmnanHG/+ mice that had been treated with a protein farnesyltransferase inhibitor (FTI) or vehicle (Veh) alone. Western blots were performed with antibodies against lamin A/C and prelamin A. Lmna+/+ fibroblasts, treated with either the FTI or the vehicle, were used as controls. Western blots were also performed with antibodies against HDJ-2, another farnesylated protein. Actin was used as a loading control. B: Quantification of lamin A levels in liver extracts of Lmna+/+, LmnaHG/+, and LmnanHG/+ mice (n = 3 mice/group; each sample was analyzed on two independent Western blots). Lamin A/actin ratios in liver extracts of FTI-treated mice were expressed relative to those in vehicle-treated mice. In the livers of Lmna+/+, LmnaHG/+, and LmnanHG/+ mice, the lamin A/actin ratio in FTI-treated mice was lower than in vehicle-treated mice (P < 0.0001). Error bars indicate SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2803242&req=5

fig2: Treatment with an FTI lowers steady-state levels of mature lamin A. A: Western blots of liver extracts from Lmna+/+, LmnaHG/+, and LmnanHG/+ mice that had been treated with a protein farnesyltransferase inhibitor (FTI) or vehicle (Veh) alone. Western blots were performed with antibodies against lamin A/C and prelamin A. Lmna+/+ fibroblasts, treated with either the FTI or the vehicle, were used as controls. Western blots were also performed with antibodies against HDJ-2, another farnesylated protein. Actin was used as a loading control. B: Quantification of lamin A levels in liver extracts of Lmna+/+, LmnaHG/+, and LmnanHG/+ mice (n = 3 mice/group; each sample was analyzed on two independent Western blots). Lamin A/actin ratios in liver extracts of FTI-treated mice were expressed relative to those in vehicle-treated mice. In the livers of Lmna+/+, LmnaHG/+, and LmnanHG/+ mice, the lamin A/actin ratio in FTI-treated mice was lower than in vehicle-treated mice (P < 0.0001). Error bars indicate SEM.
Mentions: The plasma levels of ABT-100 in treated mice were similar to those in earlier studies (12–14), ranging from 0.3 to 0.7 μg/ml. When we incubated LmnaHG/+ and LmnanHG/+ fibroblasts with the same concentration of ABT-100 that we achieved in mice (0.5 μg/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). Also, we observed, as expected, an accumulation of prelamin A and nonfarnesylated HDJ-2 in liver extracts from FTI-treated mice (Fig. 2A). Interestingly, there were lower levels of mature lamin A, relative to actin, in liver extracts from FTI-treated mice (Fig. 2A). Long-term treatment of LmnaHG/+ and LmnanHG/+ fibroblasts with ABT-100 also lowered levels of mature lamin A, consistent with the findings in FTI-treated mice (Fig. 3).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA.

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 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.

Show MeSH
Related in: MedlinePlus