Increasing the length of progerin’s isoprenyl anchor does not worsen bonedisease or survival in mice with Hutchinson-Gilford progeria syndrome

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 geranyl-geranyl lipid is ∼45-fold more potent than a farnesyl lipid in anchoring proteins to lipid membranes, we hypothesized that a geranyl-geranylated version of progerin might be more potent in eliciting disease phenotypes. To test this hypothesis, we used gene targeting to create mice expressing geranyl-geranylated progerin (Lmna^ggHG/+). We then compared Lmna^ggHG/+ mice, side-by-side, with otherwise identical mice expressing farnesylated progerin (Lmna^HG/+). Geranyl-geranylation 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. Thesteady-state levels of progerin, relative to lamin C, were lower inLmna^ggHG/+ mice than inLmna^HG/+ mice, providing a potential explanation for the milderdisease in Lmna^ggHG/+ mice.