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ID 112435
Nakazawa, Takanobu The University of Tokyo|Osaka University
Hashimoto, Ryota Osaka University
Sakoori, Kazuto The University of Tokyo
Sugaya, Yuki The University of Tokyo
Tanimura, Asami The University of Tokyo
Hashimotodani, Yuki The University of Tokyo
Ohi, Kazutaka Osaka University
Yamamori, Hidenaga Osaka University
Yasuda, Yuka Osaka University
Umeda-Yano, Satomi Osaka University
Kiyama, Yuji The University of Tokyo
Konno, Kohtarou Hokkaido University
Inoue, Takeshi The University of Tokyo
Yokoyama, Kazumasa The University of Tokyo
Inoue, Takafumi Waseda University
Ohnuma, Tohru Juntendo University
Iwata, Nakao Fujita Health University
Ozaki, Norio Nagoya University
Hashimoto, Hitoshi Osaka University
Watanabe, Masahiko Hokkaido University
Manabe, Toshiya The University of Tokyo
Yamamoto, Tadashi The University of Tokyo|Okinawa Institute of Science and Technology Graduate University
Takeda, Masatoshi Osaka University
Kano, Masanobu The University of Tokyo
Content Type
Journal Article
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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Nature Communications
Springer Nature
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Supplementary Information : ncomms_7_10594_s1.pdf
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Medical Sciences