The intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition

Maria Lidia Mignogna, Maila Giannandrea, Antonia Gurgone, Francesca Fanelli, Francesco Raimondi, Lisa Mapelli, Silvia Bassani, Huaqiang Fang, Eelco Van Anken, Massimo Alessio, Maria Passafaro, Silvia Gatti, José A. Esteban, Richard Huganir and Patrizia D’Adamo ()
Additional contact information
Maria Lidia Mignogna: Dulbecco Telethon Institute at IRCCS San Raffaele Scientific Institute
Maila Giannandrea: Dulbecco Telethon Institute at IRCCS San Raffaele Scientific Institute
Antonia Gurgone: Dulbecco Telethon Institute at IRCCS San Raffaele Scientific Institute
Francesca Fanelli: University of Modena and Reggio Emilia
Francesco Raimondi: University of Modena and Reggio Emilia
Lisa Mapelli: CNR Institute of Neuroscience, University of Milan
Silvia Bassani: CNR Institute of Neuroscience, University of Milan
Huaqiang Fang: Johns Hopkins University School of Medicine
Eelco Van Anken: IRCCS San Raffaele Scientific Institute
Massimo Alessio: IRCCS San Raffaele Scientific Institute
Maria Passafaro: CNR Institute of Neuroscience, University of Milan
Silvia Gatti: F. Hoffmann-La Roche AG, pRED Pharma Research & Early Development, DTA Neuroscience
José A. Esteban: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid
Richard Huganir: Johns Hopkins University School of Medicine
Patrizia D’Adamo: Dulbecco Telethon Institute at IRCCS San Raffaele Scientific Institute

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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 Ca2+-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.

Date: 2015
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DOI: 10.1038/ncomms7504

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