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

Takanobu Nakazawa, Ryota Hashimoto, Kazuto Sakoori, Yuki Sugaya, Asami Tanimura, Yuki Hashimotodani, Kazutaka Ohi, Hidenaga Yamamori, Yuka Yasuda, Satomi Umeda-Yano, Yuji Kiyama, Kohtarou Konno, Takeshi Inoue, Kazumasa Yokoyama, Takafumi Inoue, Shusuke Numata, Tohru Ohnuma, Nakao Iwata, Norio Ozaki, Hitoshi HashimotoMasahiko Watanabe, Toshiya Manabe, Tadashi Yamamoto, Masatoshi Takeda, Masanobu Kano

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    16 Citations (Scopus)

    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.

    Original languageEnglish
    Article number10594
    JournalNature Communications
    Volume7
    DOIs
    Publication statusPublished - 2016 Feb 3

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    ASJC Scopus subject areas

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

    Cite this

    Nakazawa, T., Hashimoto, R., Sakoori, K., Sugaya, Y., Tanimura, A., Hashimotodani, Y., Ohi, K., Yamamori, H., Yasuda, Y., Umeda-Yano, S., Kiyama, Y., Konno, K., Inoue, T., Yokoyama, K., Inoue, T., Numata, S., Ohnuma, T., Iwata, N., Ozaki, N., ... Kano, M. (2016). Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders. Nature Communications, 7, [10594]. https://doi.org/10.1038/ncomms10594