Jian Wencheng, Wei Xinbing, Chen Lin, Wang Ziying, Sun Yu, Zhu Shaowei, Lou Haiyan, Yan Shaoqi, Li Xinbing, Zhou Junlin, Zhang Bin
Department of Radiology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, People's Republic of China.
Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, People's Republic of China.
Neurosci Lett. 2017 Sep 29;658:114-120. doi: 10.1016/j.neulet.2017.08.029. Epub 2017 Aug 18.
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.
We used an in vivo 6-OHDA induced PD model and a specific HDAC6 inhibitor tubastatin A to investigate the acetylation levels of peroxiredoxin1 (Prx1) and peroxiredoxin2 (Prx2) and to explore the effects of tubastain A on nigrostriatal dopaminergic system.
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.
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.
组蛋白去乙酰化酶6（HDAC6）因其独特性质被视为一种特殊的组蛋白去乙酰化酶。它包含两个去乙酰化酶催化结构域和一个泛素结合结构域，因此对细胞功能发挥酶促和非酶促作用。迄今为止，HDAC6的泛素结合活性已涉及包括帕金森病（PD）在内的多种神经退行性疾病。然而，HDAC6在PD中的去乙酰化作用尚未得到充分阐明。因此，本研究的目的是探讨HDAC6去乙酰化活性在PD中的作用。
我们使用体内6-羟基多巴胺（6-OHDA）诱导的PD模型和一种特异性HDAC6抑制剂tubastatin A来研究过氧化物酶1（Prx1）和过氧化物酶2（Prx2）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。
我们的结果表明，6-OHDA损伤后多巴胺能神经元中HDAC6的表达显著增加。Prx1和Prx2的乙酰化水平降低。用特异性抑制剂tubastatin A对HDAC6进行药理学抑制可增加Prx1和Prx2的乙酰化，减少活性氧（ROS）生成并改善多巴胺能神经毒性。
我们的结果首次提供证据表明，HDAC6介导的Prx1和Prx2去乙酰化促成了PD中的氧化损伤，这表明需要开发特异性HDAC6抑制剂以制定更有效的治疗策略来治疗PD。
