Bach1 derepression is neuroprotective in a mouse model of Parkinson's disease.
Bach1 derepression is neuroprotective in a mouse model of Parkinson's disease.
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在帕金森病小鼠模型中，Bach1抑制具有神经保护作用。
DOI：
10.1073/pnas.2111643118
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发表时间：
2021-11-09
影响因子：
11.1
通讯作者：
Thomas B
中科院分区：
文献类型：
--
作者：
Ahuja M;Ammal Kaidery N;Attucks OC;McDade E;Hushpulian DM;Gaisin A;Gaisina I;Ahn YH;Nikulin S;Poloznikov A;Gazaryan I;Yamamoto M;Matsumoto M;Igarashi K;Sharma SM;Thomas B
Keap1-Nrf2信号通路是帕金森病（PD）的一个有希望的治疗靶点。已知靶向Keap1巯基的典型Nrf2激活剂具有预防作用，但由于其亲电性质，导致与多种细胞蛋白中的活性半胱氨酸残基发生非特异性反应，因此从未有效治疗慢性神经退行性变。我们发现，在实验性PD治疗后，Nrf2抑制因子Bach1的遗传和药理学抑制通过上调涉及Nrf2依赖的抗氧化反应元件（ARE）和非ARE基因的Bach1靶向通路，具有神经保护作用。非亲电性取代苯并咪唑抑制Bach1是一种很有前途的PD治疗方法。帕金森病（PD）是一种以黑质纹状体多巴胺能神经元丧失为特征的进行性神经退行性运动障碍。越来越多的证据表明Nrf2是PD患者神经保护干预的一个有希望的靶点。然而，典型的基于nrf2的药物的亲电化学性质导致细胞蛋白上半胱氨酸残基的不可逆烷基化，从而产生副作用。Bach1是一种已知的Nrf2通路的转录抑制因子。我们报道在PD死后大脑和临床前模型中Bach1水平上调。Bach1敲除（KO）小鼠对1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的多巴胺能神经毒性和相关的氧化损伤和神经炎症具有保护作用。功能基因组分析表明，Bach1 KO小鼠的神经保护作用是由于与nrf2依赖的抗氧化反应元件（are）和nrf2独立的非are基因相关的Bach1靶向通路的上调。使用专有的翻译技术平台，药物库筛选鉴定了取代苯并咪唑作为Bach1抑制剂，该抑制剂被验证为非亲电试剂。在治疗前后，口服Bach1抑制剂可减弱MPTP的神经毒性。Bach1抑制剂诱导的神经保护与Bach1靶向通路的上调有关，这与Bach1 KO小鼠的结果一致。我们的研究结果表明，基因缺失和非亲电抑制剂对Bach1的药理学抑制是一种很有前途的治疗PD的方法。
The Keap1-Nrf2 signaling pathway is a promising therapeutic target for Parkinson’s disease (PD). Canonical Nrf2 activators targeting Keap1 thiols are known to be preventive but never effectively cure chronic neurodegeneration because of their electrophilic nature, resulting in nonspecific reactions with active cysteine residues in a variety of cellular proteins. We show that genetic and pharmacologic inhibition of the Nrf2 repressor Bach1 in a posttreatment regimen of experimental PD is neuroprotective by up-regulating Bach1-targeted pathways involving both Nrf2-dependent antioxidant response element (ARE) and non-ARE genes. Inhibition of Bach1 by a nonelectrophilic substituted benzimidazole is a promising therapeutic approach for PD. Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by the loss of nigrostriatal dopaminergic neurons. Mounting evidence suggests that Nrf2 is a promising target for neuroprotective interventions in PD. However, electrophilic chemical properties of the canonical Nrf2-based drugs cause irreversible alkylation of cysteine residues on cellular proteins resulting in side effects. Bach1 is a known transcriptional repressor of the Nrf2 pathway. We report that Bach1 levels are up-regulated in PD postmortem brains and preclinical models. Bach1 knockout (KO) mice were protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity and associated oxidative damage and neuroinflammation. Functional genomic analysis demonstrated that the neuroprotective effects in Bach1 KO mice was due to up-regulation of Bach1-targeted pathways that are associated with both Nrf2-dependent antioxidant response element (ARE) and Nrf2-independent non-ARE genes. Using a proprietary translational technology platform, a drug library screen identified a substituted benzimidazole as a Bach1 inhibitor that was validated as a nonelectrophile. Oral administration of the Bach1 inhibitor attenuated MPTP neurotoxicity in pre- and posttreatment paradigms. Bach1 inhibitor–induced neuroprotection was associated with the up-regulation of Bach1-targeted pathways in concurrence with the results from Bach1 KO mice. Our results suggest that genetic deletion as well as pharmacologic inhibition of Bach1 by a nonelectrophilic inhibitor is a promising therapeutic approach for PD.
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影响因子：
3.5
作者：
Kaidery, Navneet Ammal;Ahuja, Manuj;Thomas, Bobby
通讯作者：
Thomas, Bobby
针对KEAP1-NRF2途径的挑战和局限性神经疗法：Bach1将抑制降低到营救。
影响因子：
4.8
作者：
Hushpulian DM;Ammal Kaidery N;Ahuja M;Poloznikov AA;Sharma SM;Gazaryan IG;Thomas B
通讯作者：
Thomas B
影响因子：
64.8
作者：
Lee, Jiyoung;Yesilkanal, Ali E.;Rosner, Marsha Rich
通讯作者：
Rosner, Marsha Rich
影响因子：
3.7
作者：
Attucks OC;Jasmer KJ;Hannink M;Kassis J;Zhong Z;Gupta S;Victory SF;Guzel M;Polisetti DR;Andrews R;Mjalli AM;Kostura MJ
通讯作者：
Kostura MJ
DOI：
10.1126/science.aan4665
发表时间：
2018-04-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kornberg MD;Bhargava P;Kim PM;Putluri V;Snowman AM;Putluri N;Calabresi PA;Snyder SH
通讯作者：
Snyder SH