Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria

V. Cenni, C. Capanni, M. Columbaro, M. Ortolani, M. R. D'Apice, G. Novelli, M. Fini, S. Marmiroli, E. Scarano, N. M. Maraldi, S. Squarzoni, S. Prencipe, G. Lattanzi

Research output: Contribution to journalArticle

Abstract

Farnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to chromatin damage and cellular senescence and ultimately causes skin and endothelial defects, bone resorption, lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying prelamin A turnover is critical for the development of clinically effective protein inhibitors that can avoid accumulation to toxic levels without impairing lamin A/C expression, which is essential for normal biological functions. Little is known about specific molecules that may target farnesylated prelamin A to elicit protein degradation. Here, we report the discovery of rapamycin as a novel inhibitor of progerin, which dramatically and selectively decreases protein levels through a mechanism involving autophagic degradation. Rapamycin treatment of progeria cells lowers progerin, as well as wild-type prelamin A levels, and rescues the chromatin phenotype of cultured fibroblasts including histone methylation status and BAF and LAP2α distribution patterns. Importantly, rapamycin treatment does not affect lamin C protein levels, but increases the relative expression of the prelamin A endoprotease ZMPSTE24. Thus, rapamycin, an antibiotic belonging to the class of macrolides, previously found to increase longevity in mouse models, can serve as a therapeutic tool, to eliminate progerin, avoid farnesylated prelamin A accumulation, and restore chromatin dynamics in progeroid laminopathies.

Original languageEnglish
Pages (from-to)200-205
Number of pages6
JournalEuropean journal of histochemistry : EJH
Volume55
Issue number4
DOIs
Publication statusPublished - 2011

Fingerprint

Progeria
Lamins
Sirolimus
Lamin Type A
Chromatin
Poisons
Therapeutics
Premature Aging
Lipodystrophy
Proteins
Cell Aging
Macrolides
Bone Resorption
Histones
Methylation
Proteolysis
prelamin A
Fibroblasts
Anti-Bacterial Agents
Phenotype

Keywords

  • Autophagy
  • Laminopathies
  • Prelamin a
  • Progeria
  • Protein degradation
  • Rapamycin

ASJC Scopus subject areas

  • Cell Biology
  • Histology
  • Biophysics

Cite this

Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria. / Cenni, V.; Capanni, C.; Columbaro, M.; Ortolani, M.; D'Apice, M. R.; Novelli, G.; Fini, M.; Marmiroli, S.; Scarano, E.; Maraldi, N. M.; Squarzoni, S.; Prencipe, S.; Lattanzi, G.

In: European journal of histochemistry : EJH, Vol. 55, No. 4, 2011, p. 200-205.

Research output: Contribution to journalArticle

Cenni, V. ; Capanni, C. ; Columbaro, M. ; Ortolani, M. ; D'Apice, M. R. ; Novelli, G. ; Fini, M. ; Marmiroli, S. ; Scarano, E. ; Maraldi, N. M. ; Squarzoni, S. ; Prencipe, S. ; Lattanzi, G. / Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria. In: European journal of histochemistry : EJH. 2011 ; Vol. 55, No. 4. pp. 200-205.
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AU - D'Apice, M. R.

AU - Novelli, G.

AU - Fini, M.

AU - Marmiroli, S.

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AU - Lattanzi, G.

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