N6-isopentenyladenosine improves nuclear shape in fibroblasts from humans with progeroid syndromes by inhibiting the farnesylation of prelamin A

Maurizio Bifulco, Alba D'Alessandro, Simona Paladino, Anna M. Malfitano, Maria Notarnicola, Maria G. Caruso, Chiara Laezza

Research output: Contribution to journalArticle

Abstract

Hutchinson-Gilford progeria syndrome is caused by mutations in the lamin A/C gene that lead to expression of a truncated, permanently farnesylated prelamin A variant called progerin. The accumulation of progerin at the nuclear envelope causes mis-shapen nuclei and results in progeroid syndromes. Previous studies in cells from individuals with Hutchinson-Gilford progeria syndrome have shown that blocking of farnesylation of prelamin A ameliorates the nuclear shape abnormalities. Here we observed that an inhibitor of farnesyl diphosphate synthase, N6-isopentenyladenosine, impeded the farnesylation of prelamin A, causing a decrease in the frequency of nuclear shape abnormalities and redistribution of prelamin A away from the inner nuclear envelope. A combination of lovastatin and N6-isopentenyladenosine significantly improved nuclear shape in fibroblast cell lines from atypical progeria patients. These findings establish a paradigm for ameliorating the most obvious cellular pathology in lamin-related progeroid syndromes, and suggest a potential strategy for treating children with Hutchinson-Gilford progeria syndrome.

Original languageEnglish
Pages (from-to)6223-6232
Number of pages10
JournalFEBS Journal
Volume280
Issue number23
DOIs
Publication statusPublished - Dec 2013

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Keywords

  • farnesyl diphosphate synthase
  • Hutchinson-Gilford progeria syndrome
  • mevalonate pathway
  • N6-isopentenyladenosine
  • prelamin A

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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