Several progeroid disorders, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by defects that lead to the accumulation of farnesyl-prelamin A at the nuclear rim. The accumulation of farnesyl-prelamin A causes grossly misshapen nuclei in cultured cells. We proposed that the farnesylated form of prelamin A is toxic to cells and predicted that inhibiting protein farnesylation would reduce the frequency of misshapen nuclei and ameliorate disease phenotypes in a pair of progeria mouse models created in our laboratory, Zmpste24-deficient mice and mice heterozygous for a HGPS """"""""knock-in"""""""" mutation (LmnaHG/+). These predictions regarding the importance of protein farnesylation were upheld: farnesyltransferase inhibitors (FTIs) reduced the frequency of misshapen nuclei in cultured cells and also ameliorated disease phenotypes in both of the progeria mouse models. These studies have been gratifying because they have suggested that FTIs could be efficacious for treating humans with HGPS. However, these studies left us with important questions regarding the mechanisms by which FTIs improve disease phenotypes. The FTI treatment was unequivocally efficacious in ameliorating disease phenotypes, yet it had only a small effect on prelamin A processing in mice. How, therefore, can an improvement in disease phenotypes be explained? One possibility is that an extremely small effect on prelamin A farnesylation is sufficient to ameliorate disease phenotypes;another is that FTIs could ameliorate disease independently of their effect on prelamin A processing.
Our first aim will be to examine this issue in detail, by analyzing additional gene-targeted mouse models and by better defining the effects of FTIs on prelamin A metabolism in vivo.
Our second aim will be to further examine an unexpected finding in our HGPS mice-that the nuclear shape abnormalities and disease phenotypes associated with the LmnaHG allele can be reduced significantly by decreasing the synthesis of wild-type lamin A (by replacing the wild-type Lmna allele in the LmnaHG/+ mice with a """"""""lamin C-only"""""""" allele). One interpretation of this finding is that wild-type prelamin A (or lamin A) worsens progeria, while lamin C does not. During the next few years, we will examine this concept in considerable detail by examining the impact of the LmnaHG allele in the presence of both a """"""""lamin C-only"""""""" allele and a """"""""lamin A-only"""""""" allele on disease phenotypes and nuclear mechanics.
Our third aim will explore the physiological impact of nonfarnesylated prelamin A. Treatment of progeria with an FTI will lead to the accumulation of nonfarnesylated prelamin A (from the wild-type Lmna allele). The properties of this abnormal protein and whether it exhibits its own toxicities are unknown. We will address this issue by analyzing nonfarnesylated prelamin A-only mice and examining the impact of the lamin protein on cell and tissue physiology.
The proposed studies will define how mutations in structural proteins of the nucleus cause premature aging, or progeria. New mouse models will be created to study the development of disease and to test a new therapeutic approach.
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