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

Research output: Contribution to journalArticle

13 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 - 03-02-2016

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knockout mice
Knockout Mice
Synapses
brain
synapses
emerging
Brain
Sorting Nexins
disorders
trkB Receptor
Nerve Growth Factor Receptors
Molecular Pathology
Pathology
Protein Transport
schizophrenia
Neurons
Schizophrenia
phenotype
Spine
spine

All Science Journal Classification (ASJC) codes

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

Cite this

Nakazawa, T., Hashimoto, R., Sakoori, K., Sugaya, Y., Tanimura, A., Hashimotodani, Y., ... 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
Nakazawa, Takanobu ; Hashimoto, Ryota ; Sakoori, Kazuto ; Sugaya, Yuki ; Tanimura, Asami ; Hashimotodani, Yuki ; Ohi, Kazutaka ; Yamamori, Hidenaga ; Yasuda, Yuka ; Umeda-Yano, Satomi ; Kiyama, Yuji ; Konno, Kohtarou ; Inoue, Takeshi ; Yokoyama, Kazumasa ; Inoue, Takafumi ; Numata, Shusuke ; Ohnuma, Tohru ; Iwata, Nakao ; Ozaki, Norio ; Hashimoto, Hitoshi ; Watanabe, Masahiko ; Manabe, Toshiya ; Yamamoto, Tadashi ; Takeda, Masatoshi ; Kano, Masanobu. / Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders. In: Nature Communications. 2016 ; Vol. 7.
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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.",
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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, Hashimoto, H, Watanabe, M, Manabe, T, Yamamoto, T, Takeda, M & Kano, M 2016, 'Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders', Nature Communications, vol. 7, 10594. https://doi.org/10.1038/ncomms10594

Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders. / Nakazawa, Takanobu; Hashimoto, Ryota; Sakoori, Kazuto; Sugaya, Yuki; Tanimura, Asami; Hashimotodani, Yuki; Ohi, Kazutaka; Yamamori, Hidenaga; Yasuda, Yuka; Umeda-Yano, Satomi; Kiyama, Yuji; Konno, Kohtarou; Inoue, Takeshi; Yokoyama, Kazumasa; Inoue, Takafumi; Numata, Shusuke; Ohnuma, Tohru; Iwata, Nakao; Ozaki, Norio; Hashimoto, Hitoshi; Watanabe, Masahiko; Manabe, Toshiya; Yamamoto, Tadashi; Takeda, Masatoshi; Kano, Masanobu.

In: Nature Communications, Vol. 7, 10594, 03.02.2016.

Research output: Contribution to journalArticle

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AU - Nakazawa, Takanobu

AU - Hashimoto, Ryota

AU - Sakoori, Kazuto

AU - Sugaya, Yuki

AU - Tanimura, Asami

AU - Hashimotodani, Yuki

AU - Ohi, Kazutaka

AU - Yamamori, Hidenaga

AU - Yasuda, Yuka

AU - Umeda-Yano, Satomi

AU - Kiyama, Yuji

AU - Konno, Kohtarou

AU - Inoue, Takeshi

AU - Yokoyama, Kazumasa

AU - Inoue, Takafumi

AU - Numata, Shusuke

AU - Ohnuma, Tohru

AU - Iwata, Nakao

AU - Ozaki, Norio

AU - Hashimoto, Hitoshi

AU - Watanabe, Masahiko

AU - Manabe, Toshiya

AU - Yamamoto, Tadashi

AU - Takeda, Masatoshi

AU - Kano, Masanobu

PY - 2016/2/3

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