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

Journal of Lipid Research

Shao H. Yang¹  H. Peter Spielmann¹  Brian J. Agnew²  Emily Farber²  Loren G. Fong³  Suzanne B. Buck³  Fuyuhiko Tamanoi⁴  Roger Lee⁴  Brandon S.J. Davies⁵  Douglas A. Andres⁵  Stephen G. Young⁵ 

[1] Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536;Molecular Probes-Invitrogen, Eugene OR 97402;Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;

关键词: protein prenylation;    progeria;    farnesylation;    geranylgeranylation;    posttranslational modifications;    lamin A;   

DOI  :  

来源: DOAJ

【 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 (LmnaggHG/+). We then compared LmnaggHG/+ mice, side-by-side, with otherwise identical mice expressing farnesylated progerin (LmnaHG/+). Geranylgeranylation of progerin in LmnaggHG/+ cells and farnesylation of progerin in LmnaHG/+ cells was confirmed by metabolic labeling. Contrary to our expectations, LmnaggHG/+ mice survived longer than LmnaHG/+ mice. The LmnaggHG/+ mice also exhibited milder bone disease. The steady-state levels of progerin, relative to lamin C, were lower in LmnaggHG/+ mice than in LmnaHG/+ mice, providing a potential explanation for the milder disease in LmnaggHG/+ mice.

【 授权许可】

Unknown