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Methylglyoxal modification of TrkB promotes synaptic plasticity and enhances resilience to chronic stress

By Ziyin Wu, Yingxue Fu, Yinfeng Yang, Chao Huang, Chunli Zheng, Zihu Guo, Zihao Yang, Xuetong Chen, Jinglin Zhu, Jinghui Wang, Xiaogang Li, Liyang Chen, Weiwei Zhou, Yangyang Chen, Jiangmei Wang, Yang Yang, Meng Jiang, Sushing Chen, Aiping Lu, Jianlin Liu, Yan Li, Shiguo Sun, Zhenzhong Wang, Wei Xiao, Yonghua Wang

Posted 04 Oct 2018
bioRxiv DOI: 10.1101/435867

Major depressive disorder (MDD) is a severe psychiatric illness that affects about 16 percent of the global population. Despite massive efforts, unravelling the pathophysiology of MDD and developing effective treatments is still a huge challenge. Here, we report a novel therapeutic axis of methylglyoxal (MGO)/tropomyosin receptor kinase B (TrkB) for treating MDD. As an endogenous metabolite, MGO was demonstrated directly binding to the extracellular domain of TrkB, provoking its dimerization and autophosphorylation. This rapidly enhances the expression of brain-derived neurotrophic factor (BDNF) and forms a BDNF-positive feedback loop. Low-dose treatment of MGO effectively promotes the hippocampal neurogenesis and exhibits sustained antidepressant effects in chronic unpredictable mild stress rat models. In addition, the modulation on MGO concentration by overexpression or inhibition of Glyoxalase 1 (GLO1) has been demonstrated associated with depression behaviors in rats. Furthermore, we also identified a natural product luteolin and its derivative lutD as potent inhibitors of GLO1 and explored their precise binding modes. Our findings reveal a novel regulatory mechanism underlying MDD and depict principles for the rational design of new antidepressants targeting GLO1.

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