Tetramethylpyrazine Nitrone Promotes the Clearance of Alpha-Synuclein via Nrf2-Mediated Ubiquitin–Proteasome System Activation

IF 3.3 4区 医学 Q2 NEUROSCIENCES
Baojian Guo, Chengyou Zheng, Jie Cao, Xiaoling Qiu, Fangcheng Luo, Haitao Li, Simon Mingyuan Lee, Xifei Yang, Gaoxiao Zhang, Yewei Sun, Zaijun Zhang, Yuqiang Wang
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引用次数: 0

Abstract

Aggregation of α-synuclein (α-syn) and α-syn cytotoxicity are hallmarks of sporadic and familial Parkinson’s disease (PD). Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent enhancement of the expression of the 20S proteasome core particles (20S CPs) and regulatory particles (RPs) increases proteasome activity, which can promote α-syn clearance in PD. Activation of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) may reduce oxidative stress by strongly inducing Nrf2 gene expression. In the present study, tetramethylpyrazine nitrone (TBN), a potent-free radical scavenger, promoted α-syn clearance by the ubiquitin–proteasome system (UPS) in cell models overexpressing the human A53T mutant α-syn. In the α-syn transgenic mice model, TBN improved motor impairment, decreased the products of oxidative damage, and down-regulated the α-syn level in the serum. TBN consistently up-regulated PGC-1α and Nrf2 expression in tested models of PD. Additionally, TBN similarly enhanced the proteasome 20S subunit beta 8 (Psmb8) expression, which is linked to chymotrypsin-like proteasome activity. Furthermore, TBN increased the mRNA levels of both the 11S RPs subunits Pa28αβ and a proteasome chaperone, known as the proteasome maturation protein (Pomp). Interestingly, specific siRNA targeting of Nrf2 blocked TBN’s effects on Psmb8, Pa28αβ, Pomp expression, and α-syn clearance. In conclusion, TBN promotes the clearance of α-syn via Nrf2-mediated UPS activation, and it may serve as a potentially disease-modifying therapeutic agent for PD.

四甲基吡嗪硝酮通过 Nrf2 介导的泛素-蛋白酶体系统激活促进α-突触核蛋白的清除
α-突触核蛋白(α-syn)的聚集和α-syn的细胞毒性是散发性和家族性帕金森病(PD)的特征。核因子(红细胞衍生 2)样 2(Nrf2)依赖于增强 20S 蛋白酶体核心颗粒(20S CPs)和调节颗粒(RPs)的表达,从而提高了蛋白酶体的活性,这可以促进帕金森病中 α-syn 的清除。激活过氧化物酶体增殖激活受体γ协同激活剂1α(PGC-1α)可通过强烈诱导Nrf2基因的表达来减轻氧化应激。在本研究中,四甲基吡嗪腈(TBN)是一种强效的自由基清除剂,它能在过表达人类 A53T 突变体 α-syn 的细胞模型中促进泛素-蛋白酶体系统(UPS)对 α-syn 的清除。在α-syn转基因小鼠模型中,TBN改善了运动障碍,减少了氧化损伤产物,并下调了血清中的α-syn水平。在测试的帕金森病模型中,TBN 可持续上调 PGC-1α 和 Nrf2 的表达。此外,TBN 还同样提高了蛋白酶体 20S 亚基 beta 8(Psmb8)的表达,这与糜蛋白酶样蛋白酶体的活性有关。此外,TBN 还提高了 11S RPs 亚基 Pa28αβ 和蛋白酶体伴侣蛋白(蛋白酶体成熟蛋白,Pomp)的 mRNA 水平。有趣的是,特异性 siRNA 靶向 Nrf2 阻断了 TBN 对 Psmb8、Pa28αβ、Pomp 表达和 α-syn 清除的影响。总之,TBN通过Nrf2介导的UPS激活促进了α-syn的清除,它可能成为一种潜在的改变帕金森病病情的治疗药物。
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来源期刊
NeuroMolecular Medicine
NeuroMolecular Medicine 医学-神经科学
CiteScore
7.10
自引率
0.00%
发文量
33
审稿时长
>12 weeks
期刊介绍: NeuroMolecular Medicine publishes cutting-edge original research articles and critical reviews on the molecular and biochemical basis of neurological disorders. Studies range from genetic analyses of human populations to animal and cell culture models of neurological disorders. Emerging findings concerning the identification of genetic aberrancies and their pathogenic mechanisms at the molecular and cellular levels will be included. Also covered are experimental analyses of molecular cascades involved in the development and adult plasticity of the nervous system, in neurological dysfunction, and in neuronal degeneration and repair. NeuroMolecular Medicine encompasses basic research in the fields of molecular genetics, signal transduction, plasticity, and cell death. The information published in NEMM will provide a window into the future of molecular medicine for the nervous system.
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