The ubiquitination of serotonin transporter in lymphoblasts derived from fluvoxamine-resistant depression patients
The ubiquitination of serotonin transporter in lymphoblasts derived from fluvoxamine-resistant depression patients
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DOI：
10.1016/j.neulet.2016.01.064
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发表时间：
2016-03
影响因子：
2.5
通讯作者：
A. Mouri;M. Ikeda;T. Koseki;N. Iwata;T. Nabeshima
中科院分区：
文献类型：
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作者：
A. Mouri;M. Ikeda;T. Koseki;N. Iwata;T. Nabeshima
抑郁症（MDD）的病理生理学中存在着多巴胺能神经元功能的不足。5-羟色胺转运体（Serotonin transporter，SERT）在终止肾上腺素能神经元的功能中起重要作用。SERT与MDD易感性有关，是抗抑郁药的重要靶点。SERT在淋巴细胞和血小板中的表达与其在中枢神经系统中的表达相关。大多数分析SERT在抑郁症中作用的临床研究都集中在脑或外周组织中SERT的绝对表达。我们的研究表明，SERT蛋白是泛素化的，这与SERT的稳定性和小鼠的抑郁行为有关。在我们的研究中，我们使用了来自外周血淋巴细胞的淋巴母细胞来定量检测氟伏沙明应答和氟伏沙明耐药MDD患者的SERT蛋白表达和泛素化。我们发现，在氟伏沙明耐药的MDD患者中，SERT蛋白水平较高。氟伏沙明耐药MDD患者的SERT泛素化蛋白水平较低。蛋白酶体抑制剂未能增加氟伏沙明反应性和氟伏沙明耐药MDD患者的SERT蛋白水平。总之，这些研究结果表明，下调SERT蛋白的泛素化诱导蛋白酶体对SERT的降解不足，这导致氟伏沙明耐药MDD患者中SERT蛋白的上调。虽然需要对不同人群进行进一步研究以概括结果，但SERT蛋白表达、泛素化和SERT表达对蛋白酶体抑制剂的反应性是诊断MDD和抗抑郁疗效的潜在生物标志物。
There is insufficient serotonergic neuronal function in the pathophysiology of major depressive disorder (MDD). Serotonin transporter (SERT) plays a critical role in terminating the function of serotoninergic neurons. SERT is linked to vulnerability to MDD and is an important target for antidepressants. The expression of SERT in lymphocytes and platelets is associated with their expression in central nervous system. Most of the clinical studies that have analyzed the role of SERT in depression have focused on absolute expression of SERT in the brain or peripheral tissue. Our study has shown that the SERT protein is ubiquitinated, which has been implicated through the SERT stability and depressive behaviors in mice. In our study, we have used lymphoblasts derived from the peripheral blood lymphocytes to quantitatively examine SERT protein expression and ubiquitination in fluvoxamine-responsive and fluvoxamine–resistant MDD patients. We found that the protein levels of SERT were higher in the fluvoxamine-resistant MDD patients. Ubiquitinated protein levels of SERT were lower in the fluvoxamine-resistant MDD patients. The proteasome inhibitor failed to increase the protein levels of SERT in both fluvoxamine-responsive and fluvoxamine-resistant MDD patients. In sum, these findings suggest that the downregulation of the ubiquitination of SERT protein induces insufficient degradation of SERT by proteasome, which resulted in the upregulation of SERT protein in fluvoxamine-resistant MDD patients. Although further studies with various populations will be required to generalize results, SERT protein expression, ubiquitination, and the responsiveness of SERT expression to proteasome inhibitor are potential biomarkers for the diagnosis of MDD and antidepressant efficacy.