Journal
FEBS JOURNAL
Volume 280, Issue 23, Pages 6223-6232Publisher
WILEY
DOI: 10.1111/febs.12544
Keywords
farnesyl diphosphate synthase; Hutchinson-Gilford progeria syndrome; mevalonate pathway; N6-isopentenyladenosine; prelaminA
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Funding
- Associazione Educazione e Ricerca Medica Salernitana
- Fondazione Italiana Sclerosi Multipla fellowship
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Hutchinson-Gilford progeria syndrome is caused by mutations in the lamin A/C gene that lead to expression of a truncated, permanently farnesylated prelaminA 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 prelaminA ameliorates the nuclear shape abnormalities. Here we observed that an inhibitor of farnesyl diphosphate synthase, N6-isopentenyladenosine, impeded the farnesylation of prelaminA, causing a decrease in the frequency of nuclear shape abnormalities and redistribution of prelaminA 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.
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