GSNOR 缺乏通过促进帕金森病小鼠模型中 CDK5 的 S-亚硝基化来减轻 MPTP 诱导的神经毒性和自噬。
GSNOR deficiency attenuates MPTP-induced neurotoxicity and autophagy by facilitating CDK5 S-nitrosation in a mouse model of Parkinson's disease.
机构信息
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Kunming, Yunnan, 650204, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China.
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
出版信息
Free Radic Biol Med. 2022 Aug 20;189:111-121. doi: 10.1016/j.freeradbiomed.2022.07.016. Epub 2022 Jul 30.
The S-nitrosoglutathione reductase (GSNOR) is a key denitrosating enzyme that regulates protein S-nitrosation, a process which has been found to be involved in the pathogenesis of Parkinson's disease (PD). However, the physiological function of GSNOR in PD remains unknown. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, we found that GSNOR expression was significantly increased and accompanied by autophagy mediated by MPTP-induced cyclin dependent kinase 5 (CDK5), behavioral dyskinesias and dopaminergic neuron loss. Whereas, knockout of GSNOR, or treatment with the GSNOR inhibitor N6022, alleviated MPTP-induced PD-like pathology and neurotoxicity. Mechanistically, deficiency of GSNOR inhibited MPTP-induced CDK5 kinase activity and CDK5-mediated autophagy by increasing S-nitrosation of CDK5 at Cys83. Our study indicated that GSNOR is a key regulator of CDK5 S-nitrosation and is actively involved in CDK5-mediated autophagy induced by MPTP.
谷胱甘肽 S-亚硝酰转移酶（GSNOR）是一种关键的脱亚硝酶，可调节蛋白质 S-亚硝基化，这一过程被发现与帕金森病（PD）的发病机制有关。然而，GSNOR 在 PD 中的生理功能仍不清楚。在 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的 PD 小鼠模型中，我们发现 GSNOR 的表达显著增加，并伴有由 MPTP 诱导的细胞周期蛋白依赖性激酶 5（CDK5）介导的自噬、行为运动障碍和多巴胺能神经元丢失。而 GSNOR 敲除或用 GSNOR 抑制剂 N6022 处理可减轻 MPTP 诱导的 PD 样病理和神经毒性。在机制上，GSNOR 的缺乏通过增加 CDK5 第 83 位半胱氨酸的 S-亚硝基化，抑制了 MPTP 诱导的 CDK5 激酶活性和 CDK5 介导的自噬。我们的研究表明，GSNOR 是 CDK5 S-亚硝酰化的关键调节剂，并且积极参与了由 MPTP 诱导的 CDK5 介导的自噬。
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