Age-Dependent Dysregulation of APP in Neuronal and Skin Cells from Fragile X Individuals
Giulia Cencelli,
Laura Pacini,
Anastasia De Luca,
Ilenia Messia,
Antonietta Gentile,
Yunhee Kang,
Veronica Nobile,
Elisabetta Tabolacci,
Peng Jin,
Maria Giulia Farace,
Claudia Bagni
Affiliations
Giulia Cencelli
Department of Biomedicine and Prevention, Faculty of Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
Laura Pacini
Department of Biomedicine and Prevention, Faculty of Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
Anastasia De Luca
Department of Biomedicine and Prevention, Faculty of Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
Ilenia Messia
Department of Biomedicine and Prevention, Faculty of Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
Antonietta Gentile
Department of Biomedicine and Prevention, Faculty of Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
Yunhee Kang
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
Veronica Nobile
Institute of Genomic Medicine, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Catholic University, 00168 Rome, Italy
Elisabetta Tabolacci
Institute of Genomic Medicine, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Catholic University, 00168 Rome, Italy
Peng Jin
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
Maria Giulia Farace
Department of Biomedicine and Prevention, Faculty of Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
Claudia Bagni
Department of Biomedicine and Prevention, Faculty of Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
Fragile X syndrome (FXS) is the most common form of monogenic intellectual disability and autism, caused by the absence of the functional fragile X messenger ribonucleoprotein 1 (FMRP). FXS features include increased and dysregulated protein synthesis, observed in both murine and human cells. Altered processing of the amyloid precursor protein (APP), consisting of an excess of soluble APPα (sAPPα), may contribute to this molecular phenotype in mice and human fibroblasts. Here we show an age-dependent dysregulation of APP processing in fibroblasts from FXS individuals, human neural precursor cells derived from induced pluripotent stem cells (iPSCs), and forebrain organoids. Moreover, FXS fibroblasts treated with a cell-permeable peptide that decreases the generation of sAPPα show restored levels of protein synthesis. Our findings suggest the possibility of using cell-based permeable peptides as a future therapeutic approach for FXS during a defined developmental window.
