All-trans retinoic acid and rapamycin normalize Hutchinson Gilford progeria fibroblast phenotype

// Camilla Pellegrini 1, 2 , Marta Columbaro 2, 3 , Cristina Capanni 1, 2 , Maria Rosaria D’Apice 4 , Carola Cavallo 3 , Michela Murdocca 5 , Giovanna Lattanzi 1, 2 , Stefano Squarzoni 1, 2 1 National Research Council of Italy, Institute of Molecular Genetics, IGM-CNR, 40136 Bologna, Italy 2 Rizzoli Orthopaedic Institute, SC Laboratory of Musculoskeletal Cell Biology, 40136 Bologna, Italy 3 Rizzoli Orthopaedic Institute, Laboratory RAMSES, 40136 Bologna, Italy 4 Fondazione Policlinico Tor Vergata, U.O.C. Laboratory of Medical Genetics, 00133 Rome, Italy 5 Tor Vergata University, Department of Biomedicine and Prevention, 00133 Rome, Italy Correspondence to: Stefano Squarzoni, e-mail: [email protected] Keywords: Hutchinson Gilford progeria syndrome, premature aging, all-trans retinoic acid, mTOR(definition)-inhibiting drug studied for extending healthspan and lifespan." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">rapamycin(definition), DNA damage and repair Received: May 13, 2015      Accepted: July 31, 2015      Published: August 13, 2015 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.