title: All-trans retinoic acid and rapamycin normalize Hutchinson Gilford progeria fibroblast phenotype.
abstract: Hutchinson Gilford progeria syndrome is a fatal disorder characterized by accelerated aging, bone resorption and atherosclerosis, caused by a LMNA mutation which produces progerin, a mutant lamin A precursor. Progeria cells display progerin and prelamin A nuclear accumulation, altered histone methylation pattern, heterochromatin loss, increased DNA damage and cell cycle alterations. Since the LMNA promoter contains a retinoic acid responsive element, we investigated if all-trans retinoic acid administration could lower progerin levels in cultured fibroblasts. We also evaluated the effect of associating rapamycin, which induces autophagic degradation of progerin and prelamin A. We demonstrate that all-trans retinoic acid acts synergistically with low-dosage rapamycin reducing progerin and prelamin A, via transcriptional downregulation associated with protein degradation, and increasing the lamin A to progerin ratio. These effects rescue cell dynamics and cellular proliferation through recovery of DNA damage response factor PARP1 and chromatin-associated nuclear envelope proteins LAP2α and BAF. The combined all-trans retinoic acid-rapamycin treatment is dramatically efficient, highly reproducible, represents a promising new approach in Hutchinson-Gilford Progeria therapy and deserves investigation in ageing-associated disorders.
authors.affiliation: National Research Council of Italy, Institute of Molecular Genetics, IGM-CNR, 40136 Bologna, Italy.|Rizzoli Orthopaedic Institute, SC Laboratory of Musculoskeletal Cell Biology, 40136 Bologna, Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Pellegrini
authors.affiliation: Rizzoli Orthopaedic Institute, SC Laboratory of Musculoskeletal Cell Biology, 40136 Bologna, Italy.|Rizzoli Orthopaedic Institute, Laboratory RAMSES, 40136 Bologna, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Columbaro
authors.affiliation: National Research Council of Italy, Institute of Molecular Genetics, IGM-CNR, 40136 Bologna, Italy.|Rizzoli Orthopaedic Institute, SC Laboratory of Musculoskeletal Cell Biology, 40136 Bologna, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Capanni
authors.affiliation: Fondazione Policlinico Tor Vergata, U.O.C. Laboratory of Medical Genetics, 00133 Rome, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: D'Apice
authors.affiliation: Rizzoli Orthopaedic Institute, Laboratory RAMSES, 40136 Bologna, Italy.
authors.forename: Carola
authors.initials: C
authors.lastname: Cavallo
authors.affiliation: Tor Vergata University, Department of Biomedicine and Prevention, 00133 Rome, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Murdocca
authors.affiliation: National Research Council of Italy, Institute of Molecular Genetics, IGM-CNR, 40136 Bologna, Italy.|Rizzoli Orthopaedic Institute, SC Laboratory of Musculoskeletal Cell Biology, 40136 Bologna, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lattanzi
authors.affiliation: National Research Council of Italy, Institute of Molecular Genetics, IGM-CNR, 40136 Bologna, Italy.|Rizzoli Orthopaedic Institute, SC Laboratory of Musculoskeletal Cell Biology, 40136 Bologna, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Squarzoni
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004357:Drug Synergism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D015870:Gene Expression / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011371:Progeria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C501959:BANF1 protein, human; D004268:DNA-Binding Proteins; D006657:Histones; D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; C093413:lamina-associated polypeptide 2; C090764:prelamin A; D014212:Tretinoin; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D008239:Lysine; D020123:Sirolimus
keywords: DNA damage and repair; Hutchinson Gilford progeria syndrome; all-trans retinoic acid; premature aging; rapamycin