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. Fong¹^,* and Stephen G. Young¹^,*^,

^* 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

Published, JLR Papers in Press, September 8, 2008.

Conflict of interest: The authors have declared that no conflictof interest exists.

This study was supported by National Institutes of Health (NIH)Grants HL76839, CA099506, and AR050200 (to S.G.Y.), HL086683(to L.G.F.), and GM66152 (to P.S.); a Senior Scholar Award inaging from The Ellison Medical Foundation (to S.G.Y.); a grantfrom the Kentucky Lung Cancer Research Program (to P.S.); anda grant from the March of Dimes (to L.G.F.). S.H.Y. was supportedby a postdoctoral fellowship grant from the Vascular BiologyProgram at UCLA (supported by the NIH) and a Beginning Grant-in-Aidfrom the American Heart Association, Western States Affiliate.

^¹ To whom correspondence should be addressed. e-mail: sgyoung{at}mednet.ucla.edu (S.G.Y.); lfong{at}mednet.ucla.edu (L.G.F.)

Hutchinson-Gilford progeria syndrome (HGPS) is caused by thesynthesis of a truncated prelamin A, commonly called progerin,that contains a carboxyl-terminal farnesyl lipid anchor. Thefarnesyl lipid anchor helps to target progerin to membrane surfacesat the nuclear rim, where it disrupts the integrity of the nuclearlamina and causes misshapen nuclei. Several lines of evidencehave suggested that progerin's farnesyl lipid anchor is crucialfor the emergence of disease phenotypes. Because a geranylgeranyllipid is $~$ 45-fold more potent than a farnesyl lipid in anchoringproteins to lipid membranes, we hypothesized that a geranylgeranylatedversion of progerin might be more potent in eliciting diseasephenotypes. To test this hypothesis, we used gene targetingto create mice expressing geranylgeranylated progerin (Lmna^ggHG/+).We then compared Lmna^ggHG/+ mice, side-by-side, with otherwiseidentical mice expressing farnesylated progerin (Lmna^HG/+).Geranylgeranylation of progerin in Lmna^ggHG/+ cells and farnesylationof progerin in Lmna^HG/+ cells was confirmed by metabolic labeling.Contrary to our expectations, Lmna^ggHG/+ mice survived longerthan Lmna^HG/+ mice. The Lmna^ggHG/+ mice also exhibited milderbone disease. The steady-state levels of progerin, relativeto lamin C, were lower in Lmna^ggHG/+ mice than in Lmna^HG/+ mice,providing a potential explanation for the milder disease inLmna^ggHG/+ mice.

Supplementary key words protein prenylation • progeria • farnesylation • geranylgeranylation • posttranslational modifications • lamin A • lamin C

Abbreviations: AG, anilinogeraniol; HGPS, Hutchinson-Gilford progeria syndrome; FTI, farnesyltransferase inhibitor; GGTI, geranylgeranyltransferase inhibitor; MEFs, mouse embryonic fibroblasts

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