title: Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation.
abstract: Hutchinson-Gilford progeria syndrome (HGPS), a progeroid syndrome in children, is caused by mutations in LMNA (the gene for prelamin A and lamin C) that result in the deletion of 50 aa within prelamin A. In normal cells, prelamin A is a "CAAX protein" that is farnesylated and then processed further to generate mature lamin A, which is a structural protein of the nuclear lamina. The mutant prelamin A in HGPS, which is commonly called progerin, retains the CAAX motif that triggers farnesylation, but the 50-aa deletion prevents the subsequent processing to mature lamin A. The presence of progerin adversely affects the integrity of the nuclear lamina, resulting in misshapen nuclei and nuclear blebs. We hypothesized that interfering with protein farnesylation would block the targeting of progerin to the nuclear envelope, and we further hypothesized that the mislocalization of progerin away from the nuclear envelope would improve the nuclear blebbing phenotype. To approach this hypothesis, we created a gene-targeted mouse model of HGPS, generated genetically identical primary mouse embryonic fibroblasts, and we then examined the effect of a farnesyltransferase inhibitor on nuclear blebbing. The farnesyltransferase inhibitor mislocalized progerin away from the nuclear envelope to the nucleoplasm, as determined by immunofluoresence microscopy, and resulted in a striking improvement in nuclear blebbing (P < 0.0001 by chi2 statistic). These studies suggest a possible treatment strategy for HGPS.
authors: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors: Shao H
authors: SH
authors: Yang
authors: Martin O
authors: MO
authors: Bergo
authors: Julia I
authors: JI
authors: Toth
authors: Xin
authors: X
authors: Qiao
authors: Yan
authors: Y
authors: Hu
authors: Salemiz
authors: S
authors: Sandoval
authors: Margarita
authors: M
authors: Meta
authors: Pravin
authors: P
authors: Bendale
authors: Michael H
authors: MH
authors: Gelb
authors: Stephen G
authors: SG
authors: Young
authors: Loren G
authors: LG
authors: Fong
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D015139:Blotting, Southern; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology*; D017931:DNA Primers; D051231:Farnesyltranstransferase; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005822:Genetic Vectors; D034904:Lamin Type A; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000235:genetics*; D011371:Progeria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011498:Protein Precursors / Q000235:genetics*; D011804:Quinolines / Q000494:pharmacology*; D017422:Sequence Analysis, DNA
chemical_list: D017931:DNA Primers; D034904:Lamin Type A; D009687:Nuclear Proteins; C504847:PB-43 compound; D011498:Protein Precursors; D011804:Quinolines; C090764:prelamin A; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase