title: The intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition.
abstract: RAB39B is a member of the RAB family of small GTPases that controls intracellular vesicular trafficking in a compartment-specific manner. Mutations in the RAB39B gene cause intellectual disability comorbid with autism spectrum disorder and epilepsy, but the impact of RAB39B loss of function on synaptic activity is largely unexplained. Here we show that protein interacting with C-kinase 1 (PICK1) is a downstream effector of GTP-bound RAB39B and that RAB39B-PICK1 controls trafficking from the endoplasmic reticulum to the Golgi and, hence, surface expression of GluA2, a subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). The role of AMPARs in synaptic transmission varies depending on the combination of subunits (GluA1, GluA2 and GluA3) they incorporate. RAB39B downregulation in mouse hippocampal neurons skews AMPAR composition towards non GluA2-containing Ca(2+)-permeable forms and thereby alters synaptic activity, specifically in hippocampal neurons. We posit that the resulting alteration in synaptic function underlies cognitive dysfunction in RAB39B-related disorders.
authors.affiliation: 1] Dulbecco Telethon Institute at IRCCS San Raffaele Scientific Institute, Division of Neuroscience, 20132 Milan, Italy [2] F. Hoffmann-La Roche AG, pRED Pharma Research &Early Development, DTA Neuroscience, CH4070 Basel, Switzerland [3] Vita-Salute San Raffaele University, 20132 Milan, Italy.
authors.forename: Maria Lidia
authors.initials: ML
authors.lastname: Mignogna
authors.affiliation: 1] Dulbecco Telethon Institute at IRCCS San Raffaele Scientific Institute, Division of Neuroscience, 20132 Milan, Italy [2] F. Hoffmann-La Roche AG, pRED Pharma Research &Early Development, DTA Neuroscience, CH4070 Basel, Switzerland.
authors.forename: Maila
authors.initials: M
authors.lastname: Giannandrea
authors.affiliation: 1] Dulbecco Telethon Institute at IRCCS San Raffaele Scientific Institute, Division of Neuroscience, 20132 Milan, Italy [2] Vita-Salute San Raffaele University, 20132 Milan, Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Gurgone
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.
authors.forename: Francesca
authors.identifier: 0000000276206895
authors.initials: F
authors.lastname: Fanelli
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Raimondi
authors.affiliation: CNR Institute of Neuroscience, Department of BIOMETRA, University of Milan, 20129 Milan, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Mapelli
authors.affiliation: CNR Institute of Neuroscience, Department of BIOMETRA, University of Milan, 20129 Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bassani
authors.affiliation: Department of Neuroscience and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Huaqiang
authors.initials: H
authors.lastname: Fang
authors.affiliation: IRCCS San Raffaele Scientific Institute, Division of Genetics and Cell Biology, 20132 Milan, Italy.
authors.forename: Eelco
authors.initials: E
authors.lastname: Van Anken
authors.affiliation: IRCCS San Raffaele Scientific Institute, Division of Genetics and Cell Biology, 20132 Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Alessio
authors.affiliation: CNR Institute of Neuroscience, Department of BIOMETRA, University of Milan, 20129 Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Passafaro
authors.affiliation: F. Hoffmann-La Roche AG, pRED Pharma Research &Early Development, DTA Neuroscience, CH4070 Basel, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Gatti
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid, Madrid 28049, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Esteban
authors.affiliation: Department of Neuroscience and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Huganir
authors.affiliation: Dulbecco Telethon Institute at IRCCS San Raffaele Scientific Institute, Division of Neuroscience, 20132 Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: D'Adamo
mesh_terms: D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism; D002522:Chlorocebus aethiops; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism; D004594:Electrophysiology; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000378:metabolism; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000737:chemistry; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission; D020798:Two-Hybrid System Techniques; D020691:rab GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D009687:Nuclear Proteins; C498297:PICk1 protein, human; D018091:Receptors, AMPA; D049452:Green Fluorescent Proteins; D006160:Guanosine Triphosphate; D005982:Glutathione Transferase; C000600250:RAB39B protein, mouse; C547812:Rab39B protein, human; D020691:rab GTP-Binding Proteins; C104722:glutamate receptor ionotropic, AMPA 2