Wencheng Jian1, Xinbing Wei2, Lin Chen2, Ziying Wang2, Yu Sun2, Shaowei Zhu3, Haiyan Lou2, Shaoqi Yan2, Xinbing Li2, Junlin Zhou2, Bin Zhang4. 1. Department of Radiology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, People's Republic of China. 2. Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, People's Republic of China. 3. Department of Neurology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, People's Republic of China. 4. Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, People's Republic of China. Electronic address: binzhang@sdu.edu.cn.
Abstract
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 peroxiredoxin1 (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.
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 peroxiredoxin1 (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-OHDAinjury. 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.
Authors: Sida Shen; Michal Svoboda; Guangming Zhang; Maria A Cavasin; Lucia Motlova; Timothy A McKinsey; James H Eubanks; Cyril Bařinka; Alan P Kozikowski Journal: ACS Med Chem Lett Date: 2020-01-15 Impact factor: 4.345
Authors: Sofie Celen; Johanna Rokka; Tonya M Gilbert; Michel Koole; Isabeau Vermeulen; Kim Serdons; Frederick A Schroeder; Florence F Wagner; Tom Bleeser; Baileigh G Hightower; Jiyun Hu; Dania Rahal; M Hassan Beyzavi; Wim Vanduffel; Koen Van Laere; Janice E Kranz; Jacob M Hooker; Guy Bormans; Christopher J Cawthorne Journal: ACS Chem Neurosci Date: 2020-03-19 Impact factor: 4.418