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

Authors

  • Maurizio Bifulco,

    1. Dipartimento di Medicina e Chirurgia, Università of Salerno Facoltà di Medicina, Baronissi, Italy
    2. Dipartimento di Farmacia, Università di Salerno, Fisciano, Italy
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    • These authors contributed equally to this work.
  • Alba D'Alessandro,

    1. Dipartimento di Medicina e Chirurgia, Università of Salerno Facoltà di Medicina, Baronissi, Italy
    2. Dipartimento di Farmacia, Università di Salerno, Fisciano, Italy
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    • These authors contributed equally to this work.
  • Simona Paladino,

    1. Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Napoli, Italy
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  • Anna M. Malfitano,

    1. Dipartimento di Medicina e Chirurgia, Università of Salerno Facoltà di Medicina, Baronissi, Italy
    2. Dipartimento di Farmacia, Università di Salerno, Fisciano, Italy
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  • Maria Notarnicola,

    1. Laboratory of Biochemistry, National Institute for Digestive Diseases, Castellana Grotte, Bari, Italy
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  • Maria G. Caruso,

    1. Laboratory of Biochemistry, National Institute for Digestive Diseases, Castellana Grotte, Bari, Italy
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  • Chiara Laezza

    Corresponding author
    1. Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Napoli, Italy
    • Correspondence

      C. Laezza, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Via Pansini 5, Napoli, Italy

      Fax/Tel: +39 817463845

      E-mail: chilaez@libero.it

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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.

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