The objective of this proposal is to use mouse models to test potential therapeutic strategies for Hutchinson-Gilford progeria syndrome (HGPS). Children with HGPS develop a host of aging-like disease phenotypes, including premature atherosclerosis. Most cases of HGPS are caused by a de novo point mutation in LMNA (the gene for prelamin A and lamin C). This mutation leads to the synthesis of a mutant prelamin A (commonly called progerin) that cannot be processed to mature lamin A by the endoprotease ZMPSTE24. Progerin is farnesylated at its carboxyl terminus. Because of the presence of this farnesyl lipid anchor, progerin accumulates at the nuclear rim (along the inner nuclear membrane) and causes grossly misshapen nuclei. Cells lacking ZMPSTE24 also accumulate farnesylated prelamin A at the nuclear rim and have grossly misshapen nuclei. We hypothesized that blocking protein farnesylation with a farnesyltransferase inhibitor (FTI) would mislocalize progerin (or prelamin A in the case of ZMPSTE24 deficiency) away from the nuclear envelope and reduce the frequency of misshapen nuclei. Indeed, this was the case, both for human and mouse cells with an HGPS mutation and for human and mouse cells lacking ZMPSTE24. These findings were extremely encouraging because they suggested a possible treatment strategy for HGPS. During the past year, we generated a mouse that produces lamin C but no lamin A or prelamin A. Remarkably, """"""""lamin C-only"""""""" mice are entirely healthy. This finding suggested that lamin A is dispensable and implied that it may be possible to treat any """"""""lamin A"""""""" disease, including HGPS, by reducing the synthesis of prelamin A/lamin A. Genetic experiments in mice have strongly supported this concept. A key goal of this proposal is to test the hypothesis that mislocalizing prelamin A or progerin away from the nuclear envelope with an FTI would prevent the progeria-like disease phenotypes in mouse models. Preliminary studies have strongly suggested that FTIs might indeed be efficacious. FTI treatment of HGPS results in the accumulation of a nonfarnesylated progerin. A second goal is to generate a new gene-targeted mouse model that expresses a nonfarnesylated version of progerin. By examining these new gene-targeted mice, we should be able to determine if the synthesis of nonfarnesylated progerin is associated with any adverse disease phenotypes. A third goal of the proposal is to determine if decreasing prelamin A synthesis with an antisense oligonucleotide could ameliorate progeria disease phenotypes in mouse models. Preliminary studies also suggest that this strategy is feasible. These studies stand a significant chance of identifying treatments for HGPS, which would be a welcome development for those affected by this disease.
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