title: Conditional depletion of intellectual disability and Parkinsonism candidate gene ATP6AP2 in fly and mouse induces cognitive impairment and neurodegeneration.
abstract: ATP6AP2, an essential accessory component of the vacuolar H+ ATPase (V-ATPase), has been associated with intellectual disability (ID) and Parkinsonism. ATP6AP2 has been implicated in several signalling pathways; however, little is known regarding its role in the nervous system. To decipher its function in behaviour and cognition, we generated and characterized conditional knockdowns of ATP6AP2 in the nervous system of Drosophila and mouse models. In Drosophila, ATP6AP2 knockdown induced defective phototaxis and vacuolated photoreceptor neurons and pigment cells when depleted in eyes and altered short- and long-term memory when depleted in the mushroom body. In mouse, conditional Atp6ap2 deletion in glutamatergic neurons (Atp6ap2(Camk2aCre/0) mice) caused increased spontaneous locomotor activity and altered fear memory. Both Drosophila ATP6AP2 knockdown and Atp6ap2(Camk2aCre/0) mice presented with presynaptic transmission defects, and with an abnormal number and morphology of synapses. In addition, Atp6ap2(Camk2aCre/0) mice showed autophagy defects that led to axonal and neuronal degeneration in the cortex and hippocampus. Surprisingly, axon myelination was affected in our mutant mice, and axonal transport alterations were observed in Drosophila. In accordance with the identified phenotypes across species, genome-wide transcriptome profiling of Atp6ap2(Camk2aCre/0) mouse hippocampi revealed dysregulation of genes involved in myelination, action potential, membrane-bound vesicles and motor behaviour. In summary, ATP6AP2 disruption in mouse and fly leads to cognitive impairment and neurodegeneration, mimicking aspects of the neuropathology associated with ATP6AP2 mutations in humans. Our results identify ATP6AP2 as an essential gene for the nervous system.
authors.affiliation: Institut Clinique de la Souris, PHENOMIN, GIE CERBM, 1 rue Laurent Fries, 67404 Illkirch, France, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France, Centre National de la Recherche Scientifique, UMR7104, Illkirch, France, Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France and Université de Strasbourg, Illkirch, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Dubos
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Anna
authors.initials: A
authors.lastname: Castells-Nobau
authors.affiliation: Institut Clinique de la Souris, PHENOMIN, GIE CERBM, 1 rue Laurent Fries, 67404 Illkirch, France.
authors.forename: Hamid
authors.initials: H
authors.lastname: Meziane
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Merel A W
authors.initials: MA
authors.lastname: Oortveld
authors.affiliation: Team Synapse in Cognition, Institut Interdisciplinaire de NeuroScience, Centre National de la Recherche Scientifique CNRS UMR5297, Université de Bordeaux, Bordeaux, France.
authors.forename: Xander
authors.initials: X
authors.lastname: Houbaert
authors.affiliation: Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Iacono
authors.affiliation: Team Synapse in Cognition, Institut Interdisciplinaire de NeuroScience, Centre National de la Recherche Scientifique CNRS UMR5297, Université de Bordeaux, Bordeaux, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Martin
authors.affiliation: Institut Clinique de la Souris, PHENOMIN, GIE CERBM, 1 rue Laurent Fries, 67404 Illkirch, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Mittelhaeuser
authors.affiliation: Institut Clinique de la Souris, PHENOMIN, GIE CERBM, 1 rue Laurent Fries, 67404 Illkirch, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Lalanne
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Kramer
authors.affiliation: Genetics, Institute of Biology, Freie Universität Berlin, Berlin, Germany.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Bhukel
authors.affiliation: Genetics, Institute of Biology, Freie Universität Berlin, Berlin, Germany, NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Quentin
authors.affiliation: VIB, Center for the Biology of Disease, Leuven, Belgium, KU Leuven, Center for Human Genetics and Leuven Institute for Neuroscience and Disease (LIND), Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Slabbert
authors.affiliation: VIB, Center for the Biology of Disease, Leuven, Belgium, KU Leuven, Center for Human Genetics and Leuven Institute for Neuroscience and Disease (LIND), Leuven, Belgium.
authors.forename: Patrik
authors.initials: P
authors.lastname: Verstreken
authors.affiliation: Genetics, Institute of Biology, Freie Universität Berlin, Berlin, Germany, NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Sigrist
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France, Centre National de la Recherche Scientifique, UMR7104, Illkirch, France, Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France and Université de Strasbourg, Illkirch, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Messaddeq
authors.affiliation: Institut Clinique de la Souris, PHENOMIN, GIE CERBM, 1 rue Laurent Fries, 67404 Illkirch, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Birling
authors.affiliation: Institut Clinique de la Souris, PHENOMIN, GIE CERBM, 1 rue Laurent Fries, 67404 Illkirch, France.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Selloum
authors.affiliation: Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
authors.forename: Henk G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: Team Synapse in Cognition, Institut Interdisciplinaire de NeuroScience, Centre National de la Recherche Scientifique CNRS UMR5297, Université de Bordeaux, Bordeaux, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Humeau
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands, annette.schenck@radboudumc.nl herault@igbmc.fr.
authors.forename: Annette
authors.initials: A
authors.lastname: Schenck
authors.affiliation: Institut Clinique de la Souris, PHENOMIN, GIE CERBM, 1 rue Laurent Fries, 67404 Illkirch, France, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France, Centre National de la Recherche Scientifique, UMR7104, Illkirch, France, Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France and Université de Strasbourg, Illkirch, France annette.schenck@radboudumc.nl herault@igbmc.fr.
authors.forename: Yann
authors.initials: Y
authors.lastname: Herault
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D003072:Cognition Disorders / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics*; D005260:Female; D055785:Gene Knockdown Techniques; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009410:Nerve Degeneration / Q000209:etiology* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D020734:Parkinsonian Disorders / Q000235:genetics; D006180:Proton-Translocating ATPases / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics*; D013569:Synapses / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D000093342:Prorenin Receptor
chemical_list: D029721:Drosophila Proteins; D008565:Membrane Proteins; D006180:Proton-Translocating ATPases; D011956:Receptors, Cell Surface; C553665:ATP6AP2 protein, Drosophila; D000093342:Prorenin Receptor; C583530:ATP6AP2 protein, mouse