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标题：Increasing the length of progerin's isoprenyl anchor does not worsen bone disease or survival in mice with Hutchinson-Gilford progeria syndrome
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作者：Brandon S. J. Davies ; Shao H. Yang ; Emily Farber 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2009
卷号：50
期号：1
页码：126-134
DOI：10.1194/jlr.M800424-JLR200
语种：English
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.