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N6‐isopentenyladenosine improves nuclear shape in fibroblasts from humans with progeroid syndromes by inhibiting the farnesylation of prelamin A
Author(s) -
Bifulco Maurizio,
D'Alessandro Alba,
Paladino Simona,
Malfitano Anna M.,
Notarnicola Maria,
Caruso Maria G.,
Laezza Chiara
Publication year - 2013
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12544
Subject(s) - progeria , lamin , prenylation , nuclear lamina , biology , nuclear protein , microbiology and biotechnology , biochemistry , gene , enzyme , transcription factor
Hutchinson– G ilford 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 H utchinson– G ilford 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, N 6‐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 N 6‐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 H utchinson– G ilford progeria syndrome.