Inhibition of HDAC6 increases acetylation of peroxiredoxin1/2 and ameliorates 6-OHDA induced dopaminergic injury
Inhibition of HDAC6 increases acetylation of peroxiredoxin1/2 and ameliorates 6-OHDA induced dopaminergic injury
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抑制 HDAC6 会增加过氧化还原蛋白 1/2 的乙酰化并改善 6-OHDA 诱导的多巴胺能损伤
DOI：
10.1016/j.neulet.2017.08.029
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发表时间：
2017-09-29
影响因子：
2.5
通讯作者：
Zhang, Bin
中科院分区：
文献类型：
--
作者：
Jian, Wencheng;Wei, Xinbing;Zhang, Bin
目的：组蛋白去乙酰化酶6（HDAC 6）因其独特的性质而被认为是一种不寻常的HDAC。它包含两个脱乙酰酶催化结构域和一个泛素结合结构域，从而对细胞功能发挥酶促和非酶促作用。迄今为止，HDAC 6的泛素结合活性已涉及几种神经退行性疾病，包括帕金森病（PD）。然而，HDAC 6在PD中的脱乙酰化作用尚未得到充分说明。方法：采用6-OHDA诱导的PD模型，应用HDAC 6特异性抑制剂tubastatin A，检测黑质纹状体多巴胺能系统中过氧化物氧还蛋白1（Peroxiredoxin 1，Prx 1）和过氧化物氧还蛋白2（Peroxiredoxin 2，Prx 2）的乙酰化水平，并探讨tubastatin A对黑质纹状体多巴胺能系统的影响。我们的研究结果表明，HDAC 6的表达显着增加多巴胺能神经元后，6-OHDA损伤。Prx 1和Prx 2的乙酰化水平降低。用特异性抑制剂tubastatin A药理学抑制HDAC 6增加了Prx 1和Prx 2的乙酰化，减少了ROS的产生并改善了多巴胺能神经毒性。我们的研究结果首次提供了证据表明HDAC 6介导的Prx 1和Prx 2的脱乙酰化有助于PD中的氧化损伤，这表明需要开发特异性HDAC 6抑制剂以开发更有效的治疗策略来治疗PD。
Objective: Histone deacetylase 6 (HDAC6) has been regarded as an unusual HDAC because of its unique properties. It contains two deacetylase catalytic domains and one ubiquitin-binding domain, thus exerting both enzymatic and non-enzymatic actions on cellular function. To date, the ubiquitin-binding activity of HDAC6 has been implicated in several neurodegenerative disorders including Parkinson's disease (PD). However, the deacetylation effect of HDAC6 in PD has not been fully illustrated. Therefore, the aim of the present study was to explore the role of deacetyation activity of HDAC6 in PD.Methods: We used an in vivo 6-OHDA induced PD model and a specific HDAC6 inhibitor tubastatin A to investigate the acetylation levels of peroxiredoxinl (Prx1) and peroxiredoxin2 (Prx2) and to explore the effects of tubastain A on nigrostriatal dopaminergic system.Results: Our results showed that expression of HDAC6 significantly increased in dopaminergic neurons after 6-OHDA injury. Acetylation levels of Prx1 and Prx2 decreased. Pharmacological inhibition of HDAC6 with specific inhibitor tubastatin A increased acetylation of Prx1 and Prx2, reduced ROS production and ameliorated dopaminergic neurotoxicity.Conclusion: Our results for the first time provide evidence that HDAC6 medicated deacetylation of Prx1 and Prx2 contributes to oxidative injury in PD, suggesting that the development of specific HDAC6 inhibitor is required to develop more effective therapeutic strategies to treat PD.