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:doi:10.18632/aging.100680

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

Vittoria Cenni^1,2,, Cristina Capanni^1,2,, Elisabetta Mattioli^1,2,, Marta Columbaro^2,, Manfred Wehnert^3,, Michela Ortolani^1,, Milena Fini^4,, Giuseppe Novelli^5,, Jessika Bertacchini^6,, Nadir M. Maraldi^1,, Sandra Marmiroli^6,, Maria Rosaria D'Apice^5,7,, Sabino Prencipe^1,2,, Stefano Squarzoni^1,2,, Giovanna Lattanzi^1,2,,

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
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Cenni V, Capanni C, Mattioli E, Columbaro M, Wehnert M, Ortolani M, Fini M, Novelli G, Bertacchini J, Maraldi NM, Marmiroli S, D'Apice MR, Prencipe S, et al, . Rapamycin treatment of Mandibuloacral Dysplasia cells rescues localization of chromatin-associated proteins and cell cycle dynamics. Aging (Albany NY). 2014; 6:755-769. https://doi.org/10.18632/aging.100680

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        TY  - JOUR
        AU  - Cenni, Vittoria 
        AU  - Capanni, Cristina 
        AU  - Mattioli, Elisabetta 
        AU  - Columbaro, Marta 
        AU  - Wehnert, Manfred 
        AU  - Ortolani, Michela 
        AU  - Fini, Milena 
        AU  - Novelli, Giuseppe 
        AU  - Bertacchini, Jessika 
        AU  - Maraldi, Nadir M. 
        AU  - Marmiroli, Sandra 
        AU  - D'Apice, Maria Rosaria 
        AU  - Prencipe, Sabino 
        AU  - Squarzoni, Stefano 
        AU  - Lattanzi, Giovanna 
        TI  - Rapamycin treatment of Mandibuloacral Dysplasia cells rescues localization of chromatin-associated proteins and cell cycle dynamics
        JO  - 
        JA  - Aging (Albany NY)
        VL  - 6
        IS  - 9
        PB  - 
        SN  - 
        UR  - https://doi.org/10.18632/aging.100680
        DO  - 10.18632/aging.100680
        SP  - 755
        EP  - 769
        PY  - 
        AB  - 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.
        ER  -

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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.

Abbreviations

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.

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

Received: April 17, 2014 Accepted: July 17, 2014 Published: July 19, 2014

Abstract

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