Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder that is 
characterized by dramatic premature aging and accelerated cardiovascular 
disease. HGPS is almost always caused by a de novo point mutation in the lamin A 
gene (LMNA) that activates a cryptic splice donor site, producing a truncated 
mutant protein termed "progerin." WT prelamin A is anchored to the nuclear 
envelope by a farnesyl isoprenoid lipid. Cleavage of the terminal 15 aa and the 
farnesyl group releases mature lamin A from this tether. In contrast, this 
cleavage site is deleted in progerin. We hypothesized that retention of the 
farnesyl group causes progerin to become permanently anchored in the nuclear 
membrane, disrupting proper nuclear scaffolding and causing the characteristic 
nuclear blebbing seen in HGPS cells. Also, we hypothesized that blocking 
farnesylation would decrease progerin toxicity. To test this hypothesis, the 
terminal CSIM sequence in progerin was mutated to SSIM, a sequence that cannot 
be farnesylated. SSIM progerin relocalized from the nuclear periphery into 
nucleoplasmic aggregates and produced no nuclear blebbing. Also, blocking 
farnesylation of authentic progerin in transiently transfected HeLa, HEK 293, 
and NIH 3T3 cells with farnesyltransferase inhibitors (FTIs) restored normal 
nuclear architecture. Last, treatment of both early- and late-passage human HGPS 
fibroblasts with FTIs resulted in significant reductions in nuclear blebbing. 
Our results suggest that treatment with FTIs represents a potential therapy for 
patients with HGPS.