Farnesylation in Experimental Progeria

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Progeria (OMIM 176670) is a disorder characterized by premature aging with early death due to coronary artery disease; it has been associated with loss-of-function mutations in LMNA (chromosome 1q21.1, OMIM 150320) encoding lamins A and C. Lamins are protein components of the inner nuclear membrane that determine the structure, size, and shape of the nucleus. Mutations in LMNA result in a product that is unable to maintain the structural and transcriptional integrity of the cell’s nucleus. Mutations in LMNA associated with progeria result in a product that is unable to undergo normal posttranslational processing of prelamin A to mature lamin A, a step that first requires addition of a 15-carbon intermediate in cholesterol synthesis termed farnesyl to a carboxyl terminal cysteine. Farnesylation of this cysteine residue facilitates movement of prelamin A to the inner nuclear membrane where the carboxyl terminal 15 amino acids including farnesylated cysteine are removed and mature lamin A incorporated into the membrane. The mutated prelamin A is directed to the rim of the nucleus where it alters nuclear form (and function). The zinc metalloproteinase ZMPSTE24 (chromosome 606480, OMIM 1p34) cleaves the terminal 15 amino acids of prelamin A converting it to mature lamin A. In vitro, inhibition of farnesylation of prelamin A in cultured fibroblasts from patients with progeroid syndromes prevents its accumulation at the nuclear rim and reduces nuclear deformation.¹ In mice carrying inactivating mutations in Zympste24 (Zympste24^-/-), a progeria-like phenotype develops.

Effect of FTI treatment on body weight. Wild-type (WT) and Zmpste24^-/- (KO) mice were given FTI (solid symbols) or vehicle alone (open symbols) beginning at 5 weeks of age. Body weights were measured weekly; the mean change in body weight from baseline for females (upper panel) and males (lower panel) is shown. The body weight curves for the FTI-treated Zmpste24^-/- mice were significantly different from those of the vehicle-treated Zmpste24^-/- mice, both in males (P < 0.0001) and in females (P < 0.0001), as judged by repeated-measures analysis of variance. Numbers of mice for each group: female wild-type mice on vehicle, n = 9; female wild-type mice on ABT-100, n = 7; male wild-type mice on vehicle, n = 5; male wild-type mice on ABT-100, n = 4; female Zmpste24^-/- mice on vehicle, n = 7; female Zmpste24^-/- mice on ABT-100, n = 7; male Zmpste24^-/- mice on vehicle, n = 7; male Zmpste24^-/- mice on ABT-100, n = 6. Error bars: SEM.

FTI treatment improves grip strength, increases survival, and reduces the number of rib fractures in Zmpste24^-/- mice. (A and B) Plots of grip strength in female and male mice over time. Zmpste24^-/- mice were given vehicle alone (open symbols) or the FTI (solid symbols) starting at 5 weeks of age. The number of mice with a grip abnormality (inability to hang upside down from a grid for 60 s) was expressed as a percentage of the total number of mice in each group. On the basis of a log rank test, the FTI significantly improved grip strength in female (P = 0.0015) and male (P = 0.036) Zmpste24^-/- mice. None of the wild-type mice developed a grip abnormality. (C) Survival of Zmpste24^-/- mice on FTI versus vehicle alone. The number of surviving male and female mice was recorded weekly and is expressed as a percentage of the total number of mice. The significance of differences was determined with a log rank test. (D) Number of rib fractures in Zmpste24^-/- mice on FTI versus vehicle alone. Wild-type and Zmpste24^-/- mice were given vehicle alone or the FTI, starting at 5 weeks of age. At 20 weeks of age, the surviving mice were killed and the number of rib fractures was counted. The number of fractured ribs in the FTI-treated Zmpste24^-/- mice was significantly lower than in the vehicle-treated Zmpste24^-/- mice (P = 0.0002), as determined by the nonparametric Kruskal-Wallis test.

In order to determine if inhibition of farnesylation in vivo might prevent development of a progeroid state, Zympste24^-/- mice were treated with an inhibitor of this enzyme (ABT-100) administered orally beginning at 5 weeks of age. Farnesylation was inhibited in vivo by ABT-100. Its administration increased weight, improved strength, decreased frequency of rib fractures, and prolonged survival in inhibitor-treated Zympste24^-/- mice relative to control Zympste24^-/- mice (Figures). However, ABT-100 did not restore Zympste24^-/- mice to normal status. The investigators concluded that inhibition of farnesylation in vivo ameliorated the progeroid phenotype in Zympste24^-/- mice.

Fong LG, Frost D, Meta M, et al. A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria. Science. 2006. 311;1621–1623.

Editor’s Comment

The findings of this study provide impetus to the development of drugs that inhibit farnesylation for the treatment of patients with progeria as well as other premature aging syndromes and perhaps even for normal aging! Indeed, 2 inhibitors of farnesylation (lonafarnib and tipifarnib), have already been studied in patients with neoplasia and seem to be well tolerated.² Interestingly, insulin-like binding protein (IGFBP)3 is a farnesyl transferase inhibitor.³ Studies of the effects of farnesylation inhibition in mice with mutations in Lmna would be of interest, as well as more directly indicative of the efficacy of such agents in an animal model of progeria.

Allen W. Root, MD

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Last Updated: 04/30/2008