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

• Published in: Aging (Albany, NY.) NY.), 2014-09, Vol.6 (9), p.755-769
• Main Authors: Cenni, Vittoria, Capanni, Cristina, Mattioli, Elisabetta, Columbaro, Marta, Wehnert, Manfred, Ortolani, Michela, Fini, Milena, Novelli, Giuseppe, Bertacchini, Jessika, Maraldi, Nadir M, Marmiroli, Sandra, D'Apice, Maria Rosaria, Prencipe, Sabino, Squarzoni, Stefano, Lattanzi, Giovanna
• Format: Article
• Language: English
• Subjects: 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; Research Paper; Sirolimus - pharmacology; Sirolimus - therapeutic use; Skin Abnormalities - metabolism
• ISSN: 1945-4589; 1945-4589
• DOI: 10.18632/aging.100680

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.