Mechanism of Tetrabenazine Regulating TH and Synaptic Vesicle Transport to Improve HD
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摘要: 通过腹腔注射3-硝基丙酸（3-NP）建立亨廷顿舞蹈症（HD）大鼠模型，探究丁苯那嗪（TBZ）改善HD样症状的作用及机制。结果显示，TBZ缓解了3-NP诱导的HD大鼠体重下降和运动障碍，逆转了纹状体中亨廷顿蛋白（Htt）的表达和神经元丢失；同时TBZ调节了纹状体中神经递质的含量，抑制酪氨酸羟化酶（TH）和囊泡单胺转运体2（VMAT2）的表达，并保护突触免受损伤；TBZ通过同时调控突触囊泡转运和TH的表达以降低纹状体中多巴胺（DA）的释放和合成，保护突触功能和神经元，从而减轻HD样症状。Abstract: As one of inherited autosomal-dominant neurodegenerative diseases, Huntington's disease (HD) is dominantly caused by an abnormally expanded CAG repeat near the N terminus of the huntingtin gene (HTT) which leads to the production of mutant huntingtin protein (mHTT). The predominant toxic gain-of-function mechanism of mHTT results in loss of striatal neurons, thereby reducing the level of dopamine (DA) in the striatum, and disrupting the balance of neurotransmitters between striatum and substantia nigra. 3-Nitropropionic acid （3-NP）is a mitochondrial toxic reagent which can damage the striatum and induce HD-like symptoms. In this study, a rat model of HD was established by intraperitoneal injection of 3-NP to investigate the effect and mechanism of tetrabenazine (TBZ) on HD-like symptoms. TBZ alleviated 3-NP-induced weight loss, dyskinesia, the expression of Htt and neuron loss. Meanwhile, it was found that TBZ regulated the content of DA and HVA in striatum by ELISA, which might be one of the reasons for the improvement of motor ability. Further mechanism study showed that TBZ inhibited the expression of tyrosine hydroxylase (TH), reducing the expression of vesicular monoamine transporter 2 (VMAT2) and enhancing synaptophysin. As a result, the synthesis and transportation of DA were reduced, protecting the synapses in the striatum. Our data suggested that TBZ reduced the release and synthesis of dopamine (DA) in the striatum by simultaneously regulating synaptic vesicular transportation and TH expression. These effects further protected neurons from damage, thereby alleviating HD-like symptoms. This study provides a new evidence for the mechanism of TBZ in the treatment of HD.
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Key words:
- Huntington’s disease /
- 3-nitropropionic acid /
- tetrabenazine /
- dopamine
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图 1 实验流程示意图
i.p—Intraperitoneal injection; i.g—Intragastric administraction
Figure 1. Experimental flow chart
图 2 TBZ逆转3-NP诱导的体重减少和异常行为
Figure 2. TBZ reversed 3-NP induced weight loss and abnormal behavior
图 3 TBZ减轻3-NP诱导的Htt蛋白水平的升高
Figure 3. TBZ reverses 3-NP-induced Htt protein upregulation
图 4 TBZ提高3-NP诱导的大鼠纹状体和黑质中神经元的存活
Figure 4. TBZ improved 3-NP - induced neuronal survival in striatum and substantia nigra
图 7 TBZ抑制3-NP诱导的突触损伤并调节VMAT2的表达水平
Figure 7. TBZ inhibited 3-NP induced synaptic damage and regulated VMAT2 expression
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