出版社：American Society for Biochemistry and Molecular Biology
摘要：Hutchinson-Gilford progeria syndrome (HGPS) is caused by the synthesis of a truncated prelamin A, commonly called progerin, that contains a carboxyl-terminal farnesyl lipid anchor. The farnesyl lipid anchor helps to target progerin to membrane surfaces at the nuclear rim, where it disrupts the integrity of the nuclear lamina and causes misshapen nuclei. Several lines of evidence have suggested that progerin's farnesyl lipid anchor is crucial for the emergence of disease phenotypes. Because a geranylgeranyl lipid is ∼45-fold more potent than a farnesyl lipid in anchoring proteins to lipid membranes, we hypothesized that a geranylgeranylated version of progerin might be more potent in eliciting disease phenotypes. To test this hypothesis, we used gene targeting to create mice expressing geranylgeranylated progerin ( Lmna ggHG/+). We then compared Lmna ggHG/+ mice, side-by-side, with otherwise identical mice expressing farnesylated progerin ( Lmna HG/+). Geranylgeranylation of progerin in Lmna ggHG/+ cells and farnesylation of progerin in Lmna HG/+ cells was confirmed by metabolic labeling. Contrary to our expectations, Lmna ggHG/+ mice survived longer than Lmna HG/+ mice. The Lmna ggHG/+ mice also exhibited milder bone disease. The steady-state levels of progerin, relative to lamin C, were lower in Lmna ggHG/+ mice than in Lmna HG/+ mice, providing a potential explanation for the milder disease in Lmna ggHG/+ mice.
