title: A paired RNAi and RabGAP overexpression screen identifies Rab11 as a regulator of β-amyloid production.
abstract: Alzheimer's disease (AD) is characterized by cerebral deposition of β-amyloid (Aβ) peptides, which are generated from amyloid precursor protein (APP) by β- and γ-secretases. APP and the secretases are membrane associated, but whether membrane trafficking controls Aβ levels is unclear. Here, we performed an RNAi screen of all human Rab-GTPases, which regulate membrane trafficking, complemented with a Rab-GTPase-activating protein screen, and present a road map of the membrane-trafficking events regulating Aβ production. We identify Rab11 and Rab3 as key players. Although retromers and retromer-associated proteins control APP recycling, we show that Rab11 controlled β-secretase endosomal recycling to the plasma membrane and thus affected Aβ production. Exome sequencing revealed a significant genetic association of Rab11A with late-onset AD, and network analysis identified Rab11A and Rab11B as components of the late-onset AD risk network, suggesting a causal link between Rab11 and AD. Our results reveal trafficking pathways that regulate Aβ levels and show how systems biology approaches can unravel the molecular complexity underlying AD.
authors.affiliation: Systems and Cell Biology of Neurodegeneration, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland; Division of Psychiatry Research, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland; Graduate Program of the Zurich Neuroscience Center, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland; Erasmus Mundus Joint Doctorate Program, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
authors.forename: Vinod
authors.initials: V
authors.lastname: Udayar
authors.affiliation: Departments of Neurobiology, Neurology and Pathology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Virginie
authors.initials: V
authors.lastname: Buggia-Prévot
authors.affiliation: Alzheimer's Exome Sequencing Group, University College London, London WC1E 6BT, UK; Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Rita L
authors.initials: RL
authors.lastname: Guerreiro
authors.affiliation: Systems and Cell Biology of Neurodegeneration, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland; Division of Psychiatry Research, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Siegel
authors.affiliation: Raise.Rural Foundation for Promoting Research Awareness in Student Environment in Rural India, 60045 Chennai, India.
authors.forename: Naresh
authors.initials: N
authors.lastname: Rambabu
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Soohoo
authors.affiliation: Raise.Rural Foundation for Promoting Research Awareness in Student Environment in Rural India, 60045 Chennai, India.
authors.forename: Moorthi
authors.initials: M
authors.lastname: Ponnusamy
authors.affiliation: Systems and Cell Biology of Neurodegeneration, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland; Division of Psychiatry Research, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Siegenthaler
authors.affiliation: Systems and Cell Biology of Neurodegeneration, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland; Division of Psychiatry Research, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland; Graduate Program of the Zurich Neuroscience Center, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
authors.forename: Jitin
authors.initials: J
authors.lastname: Bali
authors.affiliation: Department of Neurology, University of Göttingen, 37075 Göttingen, Germany; Max-Planck Institute for Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Mikael
authors.initials: M
authors.lastname: Simons
authors.affiliation: Cell Biology and Biophysics, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Ries
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
authors.forename: Manojkumar A
authors.initials: MA
authors.lastname: Puthenveedu
authors.affiliation: Alzheimer's Exome Sequencing Group, University College London, London WC1E 6BT, UK; Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Departments of Neurobiology, Neurology and Pathology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Gopal
authors.initials: G
authors.lastname: Thinakaran
authors.affiliation: Systems and Cell Biology of Neurodegeneration, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland; Division of Psychiatry Research, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland; Graduate Program of the Zurich Neuroscience Center, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland; Graduate Program of the Zurich Center for Integrative Human Physiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland. Electronic address: rajendran@bli.uzh.ch.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Rajendran
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D059472:Exome; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D021381:Protein Transport; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020692:rab3 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides; D016282:Aspartic Acid Endopeptidases; D020690:GTPase-Activating Proteins; D034741:RNA, Small Interfering; D020691:rab GTP-Binding Proteins; D020692:rab3 GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C509280:BACE1 protein, human