title: Assessing the efficacy of protein farnesyltransferase inhibitors in mouse models of progeria.
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.
authors: Department of Medicine, University of California, Los Angeles, Los Angeles, CA.
authors: Shao H
authors: SH
authors: Yang
authors: Sandy Y
authors: SY
authors: Chang
authors: Douglas A
authors: DA
authors: Andres
authors: H Peter
authors: HP
authors: Spielmann
authors: Stephen G
authors: SG
authors: Young
authors: Loren G
authors: LG
authors: Fong
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D010641:Phenotype; D054876:Prenylation / Q000187:drug effects; D011371:Progeria / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D013997:Time Factors
chemical_list: C503142:ABT-100; D004791:Enzyme Inhibitors; D007093:Imidazoles; D051231:Farnesyltranstransferase