MAGE-D1 Regulates Expression of Depression-Like Behavior through Serotonin Transporter Ubiquitylation
MAGE-D1 Regulates Expression of Depression-Like Behavior through Serotonin Transporter Ubiquitylation
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DOI：
10.1523/jneurosci.6458-11.2012
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发表时间：
2012-03-28
影响因子：
5.3
通讯作者：
Nabeshima, Toshitaka
中科院分区：
文献类型：
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作者：
Mouri, Akihiro;Sasaki, Aya;Nabeshima, Toshitaka
泛素 - 蛋白酶体系统（UPS）控制着大多数细胞蛋白质的稳定性。UPS相关基因的多态性与重度抑郁症有关，但对于通过调节UPS在抑郁症中起作用的分子知之甚少。黑色素瘤抗原基因 - D1（MAGE - D1）与环指E3泛素连接酶相互作用，并涉及蛋白质降解。因此，MAGE - D1可能通过泛素化在中枢神经系统中发挥重要作用。在此，我们阐明了MAGE - D1在情绪功能中的一种新作用，即其对血清素转运体（SERT）泛素化的调节作用。前额叶皮质中MAGE - D1基因敲除以及通过小干扰RNA（siRNA）敲低均表现出抑郁样行为，例如在原笼和新装置中的探索行为减少、社交互动减少、强迫游泳和悬尾实验中的不动时间增加以及蔗糖偏好降低，且无任何焦虑、认知或运动功能障碍。急性和慢性（28天）给予舍曲林（10 mg/kg）和丙咪嗪（20 mg/kg）可逆转基因敲除小鼠的全部或部分抑郁样行为。在这些小鼠中，前额叶皮质和海马中的血清素能功能低下，伴随着由于泛素化减少而导致的SERT过度表达。此外，MAGE - D1通过necdin同源结构域与SERT结合。细胞中MAGE - D1的过表达导致血清素摄取活性和SERT蛋白水平降低，但泛素化SERT增加。总之，目前的研究结果表明MAGE - D1在抑郁行为中具有一种新作用：调节SERT泛素化。
The ubiquitin-proteasome system (UPS) controls the stability of most cellular proteins. The polymorphism of UPS-related genes is associated with major depression disorder, but less is known about the molecule that plays a role in depression by modulating the UPS. Melanoma antigen gene-D1 (MAGE-D1) interacts with RING E3 ubiquitin ligase and is implicated in protein degradation. MAGE-D1 may thus play an important role in the CNS via ubiquitylation. Here, we clarified a novel role of MAGE-D1 in emotional functions, namely its modulation of ubiquitylation to the serotonin transporter (SERT). The MAGE-D1 knock-out and knockdown by small interfering RNA (siRNA) in the prefrontal cortex showed depression-like behavior, such as a decrease in exploratory behavior in both the home cage and novel apparatus, a decrease in social interaction, increased immobility time during forced swimming and tail suspension, and a decrease in sucrose preference without any anxiety, or cognitive or motor dysfunction. Acute and chronic (28 d) administration of sertraline (10 mg/kg) and imipramine (20 mg/kg) reversed all or part of depression-like behavior in knock-out mice. In these mice, the serotonergic function in the prefrontal cortex and hippocampus was hypoactive, accompanied by hyperexpression of SERT attributable to a decrease in ubiquitylation. Furthermore, MAGE-D1 binds to SERT via the necdin homology domain. MAGE-D1 overexpression in cells resulted in a decrease in serotonin uptake activity and the protein level of SERT but an increase in ubiquitylated SERT. Together, the present findings suggest a novel role for MAGE-D1 in depressive behaviors: modulating SERT ubiquitylation.