title: Rapamycin treatment of Mandibuloacral dysplasia cells rescues localization of chromatin-associated proteins and cell cycle dynamics.
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.
authors.affiliation: National Research Council of Italy, Institute of Molecular Genetics, IGM-CNR-IOR, Bologna, Italy. Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, Bologna, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Cenni
authors.affiliation: National Research Council of Italy, Institute of Molecular Genetics, IGM-CNR-IOR, Bologna, Italy. Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, Bologna, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Capanni
authors.affiliation: National Research Council of Italy, Institute of Molecular Genetics, IGM-CNR-IOR, Bologna, Italy. Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, Bologna, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mattioli
authors.affiliation: Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, Bologna, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Columbaro
authors.affiliation: Institute of Human Genetics, University of Greifswald, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Wehnert
authors.affiliation: National Research Council of Italy, Institute of Molecular Genetics, IGM-CNR-IOR, Bologna, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Ortolani
authors.affiliation: Rizzoli Orthopedic Institute, Laboratory of Preclinical and Surgical Studies and BITTA, RIT, Bologna, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Fini
authors.affiliation: Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Novelli
authors.affiliation: Department of Laboratory, CEIA, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Jessika
authors.initials: J
authors.lastname: Bertacchini
authors.affiliation: National Research Council of Italy, Institute of Molecular Genetics, IGM-CNR-IOR, Bologna, Italy.
authors.forename: Nadir M
authors.initials: NM
authors.lastname: Maraldi
authors.affiliation: Department of Laboratory, CEIA, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Marmiroli
authors.affiliation: Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy. Fondazione Policlinico Tor Vergata, Rome, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: D'Apice
authors.affiliation: National Research Council of Italy, Institute of Molecular Genetics, IGM-CNR-IOR, Bologna, Italy. Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, Bologna, Italy.
authors.forename: Sabino
authors.initials: S
authors.lastname: Prencipe
authors.affiliation: National Research Council of Italy, Institute of Molecular Genetics, IGM-CNR-IOR, Bologna, Italy. Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, Bologna, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Squarzoni
authors.affiliation: National Research Council of Italy, Institute of Molecular Genetics, IGM-CNR-IOR, Bologna, Italy. Rizzoli Orthopedic Institute, Laboratory of Musculoskeletal Cell Biology, Bologna, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lattanzi
mesh_terms: D030981:Acro-Osteolysis / Q000188:drug therapy* / Q000378:metabolism; D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D002843:Chromatin / Q000187:drug effects; D003286:Contracture / Q000378:metabolism / Q000151:congenital; D004260:DNA Repair / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D034904:Lamin Type A; D008060:Lipodystrophy / Q000188:drug therapy* / Q000378:metabolism; D008334:Mandible / Q000002:abnormalities* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D050811:Octamer Transcription Factor-1 / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D012868:Skin Abnormalities / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D002843:Chromatin; D004268:DNA-Binding Proteins; D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D050811:Octamer Transcription Factor-1; D011498:Protein Precursors; C093413:lamina-associated polypeptide 2; C090764:prelamin A; D020123:Sirolimus