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.

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

BIFULCO, Maurizio;MALFITANO, ANNA MARIA;
2013

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.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11386/4579662
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 8
  • Scopus 9
  • ???jsp.display-item.citation.isi??? 10
social impact