Research Paper Volume 6, Issue 9 pp 755—769
Rapamycin treatment of Mandibuloacral Dysplasia cells rescues localization of chromatin-associated proteins and cell cycle dynamics
- 1 National Research Council of Italy, Institute of Molecular Genetics, IGM-CNR-IOR, Bologna, Italy
- 2 Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, Bologna, Italy
- 3 Institute of Human Genetics, University of Greifswald, Germany
- 4 Rizzoli Orthopedic Institute, Laboratory of Preclinical and Surgical Studies and BITTA, RIT, Bologna, Italy
- 5 Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy
- 6 Department of Laboratory, CEIA, University of Modena and Reggio Emilia, Modena, Italy
- 7 Fondazione Policlinico Tor Vergata, Rome, Italy
received: April 17, 2014 ; accepted: July 17, 2014 ; published: July 19, 2014 ;https://doi.org/10.18632/aging.100680
How to Cite
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.
MADA: Mandibuloacral Dysplasia; RD: Restrictive Dermopathy; Oct-1: octamer-binding transcription factor containing a POU domain with a homeobox subdomain; LAP2 alpha: lamina-associated polypeptide 2 alpha; SIRT1: sirtuin (silent mating type information regulation 2 homolog) 1.