Reader TTS

ABSTRACT Several human progerias, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by the accumulation at the nuclear envelope of farnesylated forms of truncated prelamin A,

a protein that is also altered during normal aging1,2. Previous studies in cells from individuals with HGPS have shown that farnesyltransferase inhibitors (FTIs) improve nuclear

abnormalities associated with prelamin A accumulation, suggesting that these compounds could represent a therapeutic approach for this devastating progeroid syndrome3. We show herein that

both prelamin A and its truncated form progerin/LAΔ50 undergo alternative prenylation by geranylgeranyltransferase in the setting of farnesyltransferase inhibition, which could explain the

low efficiency of FTIs in ameliorating the phenotypes of progeroid mouse models. We also show that a combination of statins and aminobisphosphonates efficiently inhibits both farnesylation

and geranylgeranylation of progerin and prelamin A and markedly improves the aging-like phenotypes of mice deficient in the metalloproteinase Zmpste24, including growth retardation, loss of

weight, lipodystrophy, hair loss and bone defects. Likewise, the longevity of these mice is substantially extended. These findings open a new therapeutic approach for human progeroid

syndromes associated with nuclear-envelope abnormalities. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS

OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online access $209.00 per year only $17.42 per issue Learn more Buy this article * Purchase on

SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about

institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS PROGERININ, AN OPTIMIZED PROGERIN-LAMIN A BINDING INHIBITOR, AMELIORATES

PREMATURE SENESCENCE PHENOTYPES OF HUTCHINSON-GILFORD PROGERIA SYNDROME Article Open access 04 January 2021 TARGETING CK2 ELIMINATES SENESCENT CELLS AND PROLONGS LIFESPAN IN

_ZMPSTE24_-DEFICIENT MICE Article Open access 30 May 2024 A TARGETED ANTISENSE THERAPEUTIC APPROACH FOR HUTCHINSON–GILFORD PROGERIA SYNDROME Article 11 March 2021 REFERENCES * Navarro, C.L.,

Cau, P. & Levy, N. Molecular bases of progeroid syndromes. _Hum. Mol. Genet._ 15 Suppl 2, R151–R161 (2006). Article  CAS  Google Scholar  * Scaffidi, P. & Misteli, T. Lamin

A–dependent nuclear defects in human aging. _Science_ 312, 1059–1063 (2006). Article  CAS  Google Scholar  * Young, S.G., Meta, M., Yang, S.H. & Fong, L.G. Prelamin A farnesylation and

progeroid syndromes. _J. Biol. Chem._ 281, 39741–39745 (2006). Article  CAS  Google Scholar  * Kipling, D., Davis, T., Ostler, E.L. & Faragher, R.G. What can progeroid syndromes tell us

about human aging? _Science_ 305, 1426–1431 (2004). Article  CAS  Google Scholar  * Hennekam, R.C. Hutchinson-Gilford progeria syndrome: review of the phenotype. _Am. J. Med. Genet. A._ 140,

2603–2624 (2006). Article  Google Scholar  * Pendás, A.M. et al. Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase–deficient mice. _Nat.

Genet._ 31, 94–99 (2002). Article  Google Scholar  * Ramirez, C.L., Cadinanos, J., Varela, I., Freije, J.M. & López-Otín, C. Human progeroid syndromes, aging and cancer: new genetic and

epigenetic insights into old questions. _Cell. Mol. Life Sci._ 64, 155–170 (2007). Article  CAS  Google Scholar  * Varela, I. et al. Accelerated ageing in mice deficient in Zmpste24 protease

is linked to p53 signalling activation. _Nature_ 437, 564–568 (2005). Article  CAS  Google Scholar  * Liu, B. et al. Genomic instability in laminopathy-based premature aging. _Nat. Med._

11, 780–785 (2005). Article  CAS  Google Scholar  * Liu, Y., Rusinol, A., Sinensky, M., Wang, Y. & Zou, Y. DNA damage responses in progeroid syndromes arise from defective maturation of

prelamin A. _J. Cell Sci._ 119, 4644–4649 (2006). Article  CAS  Google Scholar  * Espada, J. et al. Nuclear envelope defects cause stem cell dysfunction in premature-aging mice. _J. Cell

Biol._ 181, 27–35 (2008). Article  CAS  Google Scholar  * Cadiñanos, J., Varela, I., López-Otín, C. & Freije, J.M. From immature lamin to premature aging: molecular pathways and

therapeutic opportunities. _Cell Cycle_ 4, 1732–1735 (2005). Article  Google Scholar  * Toth, J.I. et al. Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from

humans with progeroid syndromes. _Proc. Natl. Acad. Sci. USA_ 102, 12873–12878 (2005). Article  CAS  Google Scholar  * Capell, B.C. et al. Inhibiting farnesylation of progerin prevents the

characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome. _Proc. Natl. Acad. Sci. USA_ 102, 12879–12884 (2005). Article  CAS  Google Scholar  * Mallampalli, M.P., Huyer, G.,

Bendale, P., Gelb, M.H. & Michaelis, S. Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome. _Proc. Natl. Acad.

Sci. USA_ 102, 14416–14421 (2005). Article  CAS  Google Scholar  * Glynn, M.W. & Glover, T.W. Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear

abnormalities, which are reversed by farnesyltransferase inhibition. _Hum. Mol. Genet._ 14, 2959–2969 (2005). Article  CAS  Google Scholar  * Fong, L.G. et al. A protein farnesyltransferase

inhibitor ameliorates disease in a mouse model of progeria. _Science_ 311, 1621–1623 (2006). Article  CAS  Google Scholar  * Yang, S.H. et al. A farnesyltransferase inhibitor improves

disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation. _J. Clin. Invest._ 116, 2115–2121 (2006). Article  CAS  Google Scholar  * Whyte, D.B. et al. K- and N-Ras are

geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. _J. Biol. Chem._ 272, 14459–14464 (1997). Article  CAS  Google Scholar  * Rusinol, A.E. & Sinensky,

M.S. Farnesylated lamins, progeroid syndromes and farnesyl transferase inhibitors. _J. Cell Sci._ 119, 3265–3272 (2006). Article  CAS  Google Scholar  * Konstantinopoulos, P.A. &

Papavassiliou, A.G. Multilevel modulation of the mevalonate and protein-prenylation circuitries as a novel strategy for anticancer therapy. _Trends Pharmacol. Sci._ 28, 6–13 (2007). Article

  CAS  Google Scholar  * Giraudo, E., Inoue, M. & Hanahan, D. An amino-bisphosphonate targets MMP-9–expressing macrophages and angiogenesis to impair cervical carcinogenesis. _J. Clin.

Invest._ 114, 623–633 (2004). Article  CAS  Google Scholar  * Yamagata, T. et al. Effects of pravastatin in murine collagen-induced arthritis. _Rheumatol. Int._ 27, 631–639 (2007). Article 

CAS  Google Scholar  * Sullivan, T. et al. Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy. _J. Cell Biol._ 147, 913–920 (1999). Article

  CAS  Google Scholar  * Demierre, M.F., Higgins, P.D., Gruber, S.B., Hawk, E. & Lippman, S.M. Statins and cancer prevention. _Nat. Rev. Cancer_ 5, 930–942 (2005). Article  CAS  Google

Scholar  * Greenwood, J., Steinman, L. & Zamvil, S.S. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. _Nat. Rev. Immunol._ 6, 358–370 (2006). Article

  CAS  Google Scholar  * Roelofs, A.J., Thompson, K., Gordon, S. & Rogers, M.J. Molecular mechanisms of action of bisphosphonates: current status. _Clin. Cancer Res._ 12, 6222s–6230s

(2006). Article  CAS  Google Scholar  * Issat, T. et al. Potentiated antitumor effects of the combination treatment with statins and pamidronate in vitro and in vivo. _Int. J. Oncol._ 30,

1413–1425 (2007). CAS  PubMed  Google Scholar  * Schmidmaier, R., Simsek, M., Baumann, P., Emmerich, B. & Meinhardt, G. Synergistic antimyeloma effects of zoledronate and simvastatin.

_Anticancer Drugs_ 17, 621–629 (2006). Article  CAS  Google Scholar  * Blobel, G. & Potter, V.R. Nuclei from rat liver: isolation method that combines purity with high yield. _Science_

154, 1662–1665 (1966). Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We thank G. Morris (Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital) for

antibody 4A7. We thank X.S. Puente, C.L. Ramírez, A.F. Braña, P. Bourgeois, C. Massart, F. Canals, M. Barbacid, C. Guerra, K. Tryggvason, C. Stewart and G. Velasco for helpful comments and

advice and F. Rodríguez, S. Alvarez, E. Francezon, L. Espinosa and I. Bocaccio for excellent technical assistance. This work was supported by grants from Ministerio de Educación y

Ciencia-Spain, Fundación La Caixa, Fundación M. Botín, Institut National de la Santé et de la Recherche Médicale-France, Agence Nationale de la Recherche-France, Association Française contre

les Myopathies and the European Union (FP6 CancerDegradome and FP6 Eurolaminopathies). The Instituto Universitario de Oncología is supported by Obra Social Cajastur-Asturias. AUTHOR

INFORMATION AUTHORS AND AFFILIATIONS * Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, calle Fernando.

Bongera s/n, 33006-Oviedo, Spain Ignacio Varela, Alejandro P Ugalde, María F Suárez, Juan Cadiñanos, Fernando G Osorio, José M P Freije & Carlos López-Otín * Institut National de la

Sante et de la Recherche Medicale UMR_S 910, Génétique Médicale et Génomique Fonctionnelle, Université de la Méditerranée, Faculté de Médecine, Marseille Cedex 05, 13385, France Sandrine

Pereira, Claire L Navarro, Pierre Cau & Nicolas Lévy * Institut National de la Sante et de la Recherche Medicale U647, ID17, European Synchrotron Research Facility, 6 rue Jules Horowitz,

38043-Grenoble, France Nicolas Foray * Departamento de Cirugía y Especialidades Médico-Quirúrgicas, and Instituto Asturiano de Odontología, calle Julián Clavería 6, Universidad de Oviedo,

33006-Oviedo, Spain Juan Cobo & Félix de Carlos Authors * Ignacio Varela View author publications You can also search for this author inPubMed Google Scholar * Sandrine Pereira View

author publications You can also search for this author inPubMed Google Scholar * Alejandro P Ugalde View author publications You can also search for this author inPubMed Google Scholar *

Claire L Navarro View author publications You can also search for this author inPubMed Google Scholar * María F Suárez View author publications You can also search for this author inPubMed 

Google Scholar * Pierre Cau View author publications You can also search for this author inPubMed Google Scholar * Juan Cadiñanos View author publications You can also search for this author

inPubMed Google Scholar * Fernando G Osorio View author publications You can also search for this author inPubMed Google Scholar * Nicolas Foray View author publications You can also search

for this author inPubMed Google Scholar * Juan Cobo View author publications You can also search for this author inPubMed Google Scholar * Félix de Carlos View author publications You can

also search for this author inPubMed Google Scholar * Nicolas Lévy View author publications You can also search for this author inPubMed Google Scholar * José M P Freije View author

publications You can also search for this author inPubMed Google Scholar * Carlos López-Otín View author publications You can also search for this author inPubMed Google Scholar

CONTRIBUTIONS I.V., A.P.U., J. Cadiñanos, F.G.O. and J.M.P.F. carried out animal experiments. S.P., C.L.N., P.C., N.F., I.V. and A.P.U. performed cell-culture based studies. I.V., J.

Cadiñanos, J.M.P.F. and M.F.S. carried out mass spectrometry experiments. F.d.C. and J. Cobo conducted micro-CT analysis. C.L.-O., J.M.P.F., P.C. and N.L. were responsible for designing and

supervising the project and writing the manuscript. CORRESPONDING AUTHOR Correspondence to Carlos López-Otín. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TEXT AND FIGURES Supplementary Figs. 1–7

(PDF 4377 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Varela, I., Pereira, S., Ugalde, A. _et al._ Combined treatment with statins and

aminobisphosphonates extends longevity in a mouse model of human premature aging. _Nat Med_ 14, 767–772 (2008). https://doi.org/10.1038/nm1786 Download citation * Received: 25 February 2008

* Accepted: 15 May 2008 * Published: 29 June 2008 * Issue Date: July 2008 * DOI: https://doi.org/10.1038/nm1786 SHARE THIS ARTICLE Anyone you share the following link with will be able to

read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing

initiative