Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes

Julia I. Toth, Shao H. Yang, Xin Qiao, Anne P. Beigneux, Michael H. Gelb, Casey L. Moulson, Jeffrey H. Miner, Stephen G. Young, Loren G. Fong

Research output: Contribution to journalArticle

206 Scopus citations

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 Zmpsfe24-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.

Original languageEnglish
Pages (from-to)12873-12878
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number36
DOIs
StatePublished - Sep 6 2005

Keywords

  • Aging
  • Hutchinson-Gilford progeria syndrome
  • Lamin
  • Restrictive dermopathy
  • ZMPSTE24

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