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Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders

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  • Takanobu Nakazawa

    (Graduate School of Medicine, The University of Tokyo
    Institute of Medical Science, The University of Tokyo
    iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University)

  • Ryota Hashimoto

    (Osaka University Graduate School of Medicine
    Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University)

  • Kazuto Sakoori

    (Graduate School of Medicine, The University of Tokyo)

  • Yuki Sugaya

    (Graduate School of Medicine, The University of Tokyo)

  • Asami Tanimura

    (Graduate School of Medicine, The University of Tokyo)

  • Yuki Hashimotodani

    (Graduate School of Medicine, The University of Tokyo)

  • Kazutaka Ohi

    (Osaka University Graduate School of Medicine)

  • Hidenaga Yamamori

    (Osaka University Graduate School of Medicine
    Osaka University Graduate School of Medicine)

  • Yuka Yasuda

    (Osaka University Graduate School of Medicine)

  • Satomi Umeda-Yano

    (Osaka University Graduate School of Medicine)

  • Yuji Kiyama

    (Institute of Medical Science, The University of Tokyo)

  • Kohtarou Konno

    (Hokkaido University Graduate School of Medicine)

  • Takeshi Inoue

    (Institute of Medical Science, The University of Tokyo)

  • Kazumasa Yokoyama

    (Institute of Medical Science, The University of Tokyo)

  • Takafumi Inoue

    (School of Advanced Science and Engineering, Waseda University)

  • Shusuke Numata

    (Course of Integrated Brain Sciences, School of Medicine, University of Tokushima)

  • Tohru Ohnuma

    (Juntendo University School of Medicine)

  • Nakao Iwata

    (Fujita Health University School of Medicine)

  • Norio Ozaki

    (Nagoya University Graduate School of Medicine)

  • Hitoshi Hashimoto

    (iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University
    Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University
    Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University)

  • Masahiko Watanabe

    (Hokkaido University Graduate School of Medicine)

  • Toshiya Manabe

    (Institute of Medical Science, The University of Tokyo)

  • Tadashi Yamamoto

    (Institute of Medical Science, The University of Tokyo
    Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University)

  • Masatoshi Takeda

    (Osaka University Graduate School of Medicine
    Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University)

  • Masanobu Kano

    (Graduate School of Medicine, The University of Tokyo)

Abstract

Intracellular trafficking of receptor proteins is essential for neurons to detect various extracellular factors during the formation and refinement of neural circuits. However, the precise mechanisms underlying the trafficking of neurotrophin receptors to synapses remain elusive. Here, we demonstrate that a brain-enriched sorting nexin, ARHGAP33, is a new type of regulator for the intracellular trafficking of TrkB, a high-affinity receptor for brain-derived neurotrophic factor. ARHGAP33 knockout (KO) mice exhibit reduced expression of synaptic TrkB, impaired spine development and neuropsychiatric disorder-related behavioural abnormalities. These deficits are rescued by specific pharmacological enhancement of TrkB signalling in ARHGAP33 KO mice. Mechanistically, ARHGAP33 interacts with SORT1 to cooperatively regulate TrkB trafficking. Human ARHGAP33 is associated with brain phenotypes and reduced SORT1 expression is found in patients with schizophrenia. We propose that ARHGAP33/SORT1-mediated TrkB trafficking is essential for synapse development and that the dysfunction of this mechanism may be a new molecular pathology of neuropsychiatric disorders.

Suggested Citation

  • Takanobu Nakazawa & Ryota Hashimoto & Kazuto Sakoori & Yuki Sugaya & Asami Tanimura & Yuki Hashimotodani & Kazutaka Ohi & Hidenaga Yamamori & Yuka Yasuda & Satomi Umeda-Yano & Yuji Kiyama & Kohtarou K, 2016. "Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders," Nature Communications, Nature, vol. 7(1), pages 1-17, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10594
    DOI: 10.1038/ncomms10594
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