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

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.