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

Brandon S.J. Davies; Shao H. Yang; Emily Farber; Roger Lee; Suzanne B. Buck; Douglas A. Andres; H. Peter Spielmann; Brian J. Agnew; Fuyuhiko Tamanoi; Loren G. Fong; Stephen G. Young

Journal of Lipid Research (Jan 2009)

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

Brandon S.J. Davies,
Shao H. Yang,
Emily Farber,
Roger Lee,
Suzanne B. Buck,
Douglas A. Andres,
H. Peter Spielmann,
Brian J. Agnew,
Fuyuhiko Tamanoi,
Loren G. Fong,
Stephen G. Young

Affiliations

Brandon S.J. Davies: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; 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; Molecular Probes-Invitrogen, Eugene OR 97402; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536
Shao H. Yang: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; 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; Molecular Probes-Invitrogen, Eugene OR 97402; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536
Emily Farber: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; 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; Molecular Probes-Invitrogen, Eugene OR 97402; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536
Roger Lee: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; 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; Molecular Probes-Invitrogen, Eugene OR 97402; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536
Suzanne B. Buck: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; 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; Molecular Probes-Invitrogen, Eugene OR 97402; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536
Douglas A. Andres: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; 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; Molecular Probes-Invitrogen, Eugene OR 97402; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536
H. Peter Spielmann: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; 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; Molecular Probes-Invitrogen, Eugene OR 97402; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536
Brian J. Agnew: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; 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; Molecular Probes-Invitrogen, Eugene OR 97402; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536
Fuyuhiko Tamanoi: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; 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; Molecular Probes-Invitrogen, Eugene OR 97402; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536
Loren G. Fong: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; 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; Molecular Probes-Invitrogen, Eugene OR 97402; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536
Stephen G. Young: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; 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; Molecular Probes-Invitrogen, Eugene OR 97402; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536

Journal volume & issue: Vol. 50, no. 1
pp. 126 – 134

Abstract

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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.

Published in Journal of Lipid Research

ISSN: 0022-2275 (Print); 1539-7262 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Chemistry: Organic chemistry: Biochemistry
Website: https://www.journals.elsevier.com/journal-of-lipid-research

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