Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders.
Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders.
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DOI：
10.1038/ncomms10594
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发表时间：
2016-02-03
影响因子：
16.6
通讯作者：
Kano M
中科院分区：
文献类型：
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作者：
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
在神经回路的形成和完善过程中，受体蛋白的细胞内运输对于神经元检测各种细胞外因子是必不可少的。然而，神经营养因子受体运输到突触的确切机制仍然难以捉摸。在这里，我们证明了大脑富集的分选连接蛋白，ARHGAP 33，是一种新型的调节器的TrkB，脑源性神经营养因子的高亲和力受体的细胞内贩运。ARHGAP 33敲除（KO）小鼠表现出突触TrkB表达减少、脊柱发育受损和神经精神疾病相关的行为异常。这些缺陷通过ARHGAP 33 KO小鼠中TrkB信号传导的特异性药理学增强来挽救。在机制上，ARHGAP 33与SORT 1相互作用以协同调节TrkB贩运。人类ARHGAP 33与大脑表型相关，在精神分裂症患者中发现SORT 1表达减少。我们认为ARHGAP 33/SORT 1介导的TrkB转运对突触发育至关重要，这种机制的功能障碍可能是神经精神疾病的一种新的分子病理学。 神经营养因子受体运输的分子机制仅部分了解。在这里，作者表明ARHGAP 33与SORT 1相互作用以调节TrkB运输，其功能障碍会损害突触发育并导致小鼠精神分裂症相关的行为异常。
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. The molecular mechanisms of neurotrophin receptor trafficking are only partially understood. Here the authors show that ARHGAP33 interacts with SORT1 to regulate TrkB trafficking, the dysfunction of which impairs synapse development and leads to schizophrenia-related behavioural abnormalities in mice.