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

  • V. Cenni National Research Council of Italy, Italy.
  • C. Capanni National Research Council of Italy, Italy.
  • M. Columbaro Rizzoli Orthopedic Institute, Italy.
  • M. Ortolani National Research Council of Italy, Italy.
  • M.R. D'Apice University of Tor Vergata, Rome, Italy.
  • G. Novelli University of Tor Vergata, Rome, Italy.
  • M. Fini Rizzoli Orthopedic Institute and BITTA, RIT, IOR, Italy.
  • S. Marmiroli University of Modena and Reggio Emilia, Italy.
  • E. Scarano S. Orsola-Malpighi Hospital, University of Bologna, Italy.
  • N.M. Maraldi Rizzoli Orthopedic Institute, Italy.
  • S. Squarzoni National Research Council of Italy, Italy.
  • S. Prencipe Rizzoli Orthopedic Institute and BITTA, RIT, IOR, Italy.
  • G. Lattanzi | lattanzi@area.bo.cnr.it National Research Council of Italy, Italy.

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 LAP2alpha 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.

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Author Biographies

V. Cenni, National Research Council of Italy
Institute for Molecular Genetics, IGM-CNR, Unit of Bologna c/o IOR
C. Capanni, National Research Council of Italy
Institute for Molecular Genetics, IGM-CNR, Unit of Bologna c/o IOR
M. Columbaro, Rizzoli Orthopedic Institute
Laboratory of Musculoskeletal Cell Biology
M. Ortolani, National Research Council of Italy
Institute for Molecular Genetics, IGM-CNR, Unit of Bologna c/o IOR
M.R. D'Apice, University of Tor Vergata, Rome
Department of Biopathology and Diagnostic Imaging
G. Novelli, University of Tor Vergata, Rome
Department of Biopathology and Diagnostic Imaging
M. Fini, Rizzoli Orthopedic Institute and BITTA, RIT, IOR
Laboratory of Preclinical and Surgical Studies
S. Marmiroli, University of Modena and Reggio Emilia
Department of Histology
E. Scarano, S. Orsola-Malpighi Hospital, University of Bologna
Department of Pediatrics
N.M. Maraldi, Rizzoli Orthopedic Institute
Laboratory of Musculoskeletal Cell Biology
S. Squarzoni, National Research Council of Italy
Institute for Molecular Genetics, IGM-CNR, Unit of Bologna c/o IOR
S. Prencipe, Rizzoli Orthopedic Institute and BITTA, RIT, IOR
Laboratory of Preclinical and Surgical Studies
G. Lattanzi, National Research Council of Italy
Institute for Molecular Genetics, IGM-CNR, Unit of Bologna c/o IOR
Published
2011-10-19
Section
Original Papers
Supporting Agencies
Italian MIUR PRIN 2008, Italian MIUR FIRB 2010, Fondazione CarisBo, ITALY, A.I.Pro.Sa.B.
Keywords:
prelamin A, autophagy, protein degradation, laminopathies, progeria, Rapamycinprelamin A, Rapamycin
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How to Cite
Cenni, V., Capanni, C., Columbaro, M., Ortolani, M., D’Apice, M., Novelli, G., Fini, M., Marmiroli, S., Scarano, E., Maraldi, N., Squarzoni, S., Prencipe, S., & Lattanzi, G. (2011). Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria. European Journal of Histochemistry, 55(4), e36. https://doi.org/10.4081/ejh.2011.e36