Rapamycin treatment of Mandibuloacral dysplasia cells rescues localization of chromatin-associated proteins and cell cycle dynamics

Vittoria Cenni; Cristina Capanni; Elisabetta Mattioli; Marta Columbaro; Manfred Wehnert; Michela Ortolani; Milena Fini; Giuseppe Novelli; Jessika Bertacchini; Nadir M Maraldi; Sandra Marmiroli; Maria Rosaria D'Apice; Sabino Prencipe; Stefano Squarzoni; Giovanna Lattanzi

doi:10.18632/aging.100680

Rapamycin treatment of Mandibuloacral dysplasia cells rescues localization of chromatin-associated proteins and cell cycle dynamics

Aging (Albany NY). 2014 Sep;6(9):755-70. doi: 10.18632/aging.100680.

Authors

Affiliations

¹ National Research Council of Italy, Institute of Molecular Genetics, IGM-CNR-IOR, Bologna, Italy. Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, Bologna, Italy.
² Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, Bologna, Italy.
³ Institute of Human Genetics, University of Greifswald, Germany.
⁴ National Research Council of Italy, Institute of Molecular Genetics, IGM-CNR-IOR, Bologna, Italy.
⁵ Rizzoli Orthopedic Institute, Laboratory of Preclinical and Surgical Studies and BITTA, RIT, Bologna, Italy.
⁶ Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy.
⁷ Department of Laboratory, CEIA, University of Modena and Reggio Emilia, Modena, Italy.
⁸ Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy. Fondazione Policlinico Tor Vergata, Rome, Italy.

Abstract

Lamin A is a key component of the nuclear lamina produced through post-translational processing of its precursor known as prelamin A.LMNA mutations leading to farnesylated prelamin A accumulation are known to cause lipodystrophy, progeroid and developmental diseases, including Mandibuloacral dysplasia, a mild progeroid syndrome with partial lipodystrophy and altered bone turnover. Thus, degradation of prelamin A is expected to improve the disease phenotype. Here, we show different susceptibilities of prelamin A forms to proteolysis and further demonstrate that treatment with rapamycin efficiently and selectively triggers lysosomal degradation of farnesylated prelamin A, the most toxic processing intermediate. Importantly, rapamycin treatment of Mandibuloacral dysplasia cells, which feature very low levels of the NAD-dependent sirtuin SIRT-1 in the nuclear matrix, restores SIRT-1 localization and distribution of chromatin markers, elicits release of the transcription factor Oct-1 and determines shortening of the prolonged S-phase. These findings indicate the drug as a possible treatment for Mandibuloacral dysplasia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acro-Osteolysis / drug therapy*
Acro-Osteolysis / metabolism
Adult
Antibiotics, Antineoplastic / pharmacology
Antibiotics, Antineoplastic / therapeutic use*
Cell Cycle / drug effects
Cells, Cultured
Chromatin / drug effects
Contracture / metabolism
DNA Repair / drug effects
DNA-Binding Proteins / metabolism
Fibroblasts / drug effects
Fibroblasts / metabolism
Humans
Infant, Newborn
Lamin Type A
Lipodystrophy / drug therapy*
Lipodystrophy / metabolism
Mandible / abnormalities*
Mandible / metabolism
Membrane Proteins / metabolism
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Octamer Transcription Factor-1 / metabolism*
Protein Precursors / genetics
Protein Precursors / metabolism*
Sirolimus / pharmacology
Sirolimus / therapeutic use*
Skin Abnormalities / metabolism

Substances

Antibiotics, Antineoplastic
Chromatin
DNA-Binding Proteins
Lamin Type A
Membrane Proteins
Nuclear Proteins
Octamer Transcription Factor-1
Protein Precursors
lamina-associated polypeptide 2
prelamin A
Sirolimus

Supplementary concepts

Mandibuloacral dysplasia with type A lipodystrophy
Tight skin contracture syndrome, lethal