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EnglishHutchinson-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.
| Titolo: | N6-isopentenyladenosine improves nuclear shape in fibroblasts from humans with progeroid syndromes by inhibiting the farnesylation of prelamin A |
| Autori: | |
| Data di pubblicazione: | 2013 |
| Rivista: | |
| 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. |
| Handle: | http://hdl.handle.net/11386/4579662 |
| Appare nelle tipologie: | 1.1.1 Articolo su rivista con DOI |
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