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, Patrizia D'Adamo

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number6504
JournalNature communications
Volume6
DOIs
StatePublished - Mar 18 2015

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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