title: Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes.
abstract: Defects in the biogenesis of lamin A from its farnesylated precursor, prelamin A, lead to the accumulation of prelamin A at the nuclear envelope, cause misshapen nuclei, and result in progeroid syndromes. A deficiency in ZMPSTE24, a protease involved in prelamin A processing, leads to prelamin A accumulation, an absence of mature lamin A, misshapen nuclei, and a lethal perinatal progeroid syndrome: restrictive dermopathy (RD). Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutant prelamin A that cannot be processed to lamin A. The hallmark cellular abnormality in RD and HGPS is misshapen nuclei. We hypothesized that the farnesylation of prelamin A is important for its targeting to the nuclear envelope in RD and HGPS and that blocking farnesylation would ameliorate the nuclear shape abnormalities. Indeed, when RD fibroblasts were treated with a farnesyltransferase inhibitor (FTI), prelamin A was partially mislocalized away from the nuclear envelope, and the frequency of nuclear shape abnormalities was reduced (P < 0.0001). A FTI also mislocalized prelamin A and improved nuclear shape in Zmpste24-deficient mouse embryonic fibroblasts (P < 0.0001) and improved nuclear shape in human HGPS fibroblasts (P < 0.0001). Most remarkably, a FTI significantly improved nuclear shape in two fibroblast cell lines from atypical progeria patients with lamin A missense mutations in the absence of prelamin A accumulation (P = 0.0003 and P < 0.0001). These findings establish a paradigm for ameliorating the most obvious cellular pathology in lamin-related progeroid syndromes and suggest a potential strategy for treating these diseases.
authors.affiliation: Department of Medicine and Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Julia I
authors.initials: JI
authors.lastname: Toth
authors.forename: Shao H
authors.initials: SH
authors.lastname: Yang
authors.forename: Xin
authors.initials: X
authors.lastname: Qiao
authors.forename: Anne P
authors.initials: AP
authors.lastname: Beigneux
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
authors.forename: Casey L
authors.initials: CL
authors.lastname: Moulson
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Miner
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
authors.forename: Loren G
authors.initials: LG
authors.lastname: Fong
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase; D005347:Fibroblasts / Q000166:cytology*; D006801:Humans; D034904:Lamin Type A; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D011371:Progeria / Q000201:enzymology* / Q000473:pathology*; D011498:Protein Precursors / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D008666:Metalloendopeptidases; C491250:Zmpste24 protein, mouse