title: Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome.
abstract: The Fragile X mental retardation protein (FMRP) regulates neuronal RNA metabolism, and its absence or mutations leads to the Fragile X syndrome (FXS). The β-amyloid precursor protein (APP) is involved in Alzheimer's disease, plays a role in synapse formation, and is upregulated in intellectual disabilities. Here, we show that during mouse synaptogenesis and in human FXS fibroblasts, a dual dysregulation of APP and the α-secretase ADAM10 leads to the production of an excess of soluble APPα (sAPPα). In FXS, sAPPα signals through the metabotropic receptor that, activating the MAP kinase pathway, leads to synaptic and behavioral deficits. Modulation of ADAM10 activity in FXS reduces sAPPα levels, restoring translational control, synaptic morphology, and behavioral plasticity. Thus, proper control of ADAM10-mediated APP processing during a specific developmental postnatal stage is crucial for healthy spine formation and function(s). Downregulation of ADAM10 activity at synapses may be an effective strategy for ameliorating FXS phenotypes.
authors.affiliation: Center for Human Genetics and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium; VIB Center for the Biology of Disease, 3000 Leuven, Belgium.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Pasciuto
authors.affiliation: Faculty of Psychology and Educational Sciences, Laboratory of Biological Psychology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Tariq
authors.initials: T
authors.lastname: Ahmed
authors.affiliation: Center for Human Genetics and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium; VIB Center for the Biology of Disease, 3000 Leuven, Belgium.
authors.forename: Tina
authors.initials: T
authors.lastname: Wahle
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari and Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, 20133 Milan, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gardoni
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: D'Andrea
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Pacini
authors.affiliation: Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland; Department of Psychiatry, University of Montreal, QC H3T 1C5, Canada; Centre de Recherche, Centre Hospitalier Universitaire Sainte Justine, Montréal, QC H3T 1C4, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jacquemont
authors.affiliation: Department of Biochemistry and Molecular Medicine, UC Davis, Sacramento, CA 95817, USA; MIND Institute, UC Davis Medical Center, Sacramento, CA 95817, USA.
authors.forename: Flora
authors.initials: F
authors.lastname: Tassone
authors.affiliation: Faculty of Psychology and Educational Sciences, Laboratory of Biological Psychology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Detlef
authors.initials: D
authors.lastname: Balschun
authors.affiliation: Center for Human Genetics and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium; VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Centro de Biología Molecular Severo Ochoa, CSIC/UAM, 28049 Madrid, Spain.
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Dotti
authors.affiliation: Faculty of Psychology and Educational Sciences, Laboratory of Biological Psychology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Callaerts-Vegh
authors.affiliation: Faculty of Psychology and Educational Sciences, Laboratory of Biological Psychology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.affiliation: Institute for Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Ulrike C
authors.initials: UC
authors.lastname: Müller
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari and Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, 20133 Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Di Luca
authors.affiliation: Center for Human Genetics and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium; VIB Center for the Biology of Disease, 3000 Leuven, Belgium; UCL Institute of Neurology, Queen Square, WC1N 3BG London, UK.
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.affiliation: Center for Human Genetics and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium; VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy. Electronic address: claudia.bagni@cme.vib-kuleuven.be.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bagni
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002648:Child; D005260:Female; D005600:Fragile X Syndrome / Q000235:genetics / Q000473:pathology*; D005786:Gene Expression Regulation / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D013569:Synapses / Q000473:pathology*; D013997:Time Factors; D055815:Young Adult
chemical_list: D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human