Toxicogenomics and Predictive Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, Uttar Pradesh, India.
Mol Neurobiol. 2024 Feb;61(2):953-970. doi: 10.1007/s12035-023-03591-6. Epub 2023 Sep 6.
Cypermethrin impairs mitochondrial function, induces redox imbalance, and leads to Parkinsonism in experimental animals. Knockdown of deglycase-1 (DJ-1) gene, which encodes a redox-sensitive antioxidant protein, aggravates cypermethrin-mediated α-synuclein overexpression and oxidative alteration of proteins. DJ-1 is also reported to be essential for maintaining stability of nuclear factor erythroid 2-related factor 2 (Nrf2), shielding cells against oxidative insult. Leucine-rich repeat kinase 2 (LRRK2), another protein associated with Parkinson's disease, is also involved in regulating mitochondrial function. However, underlying molecular mechanisms remain elusive. The study intended to explore an interaction of DJ-1, LRRK2, and Nrf2 in the regulation of mitochondrial function in cypermethrin-induced Parkinsonism. Small interfering RNA-mediated knockdown of DJ-1 and LRRK2 gene and pharmacological activation of Nrf2 were performed in rats and/or human neuroblastoma cells with or without cypermethrin. Indexes of oxidative stress, mitochondrial impairment, and Parkinsonism along with α-synuclein expression, post-translational modification, and aggregation were measured. DJ-1 gene knockdown exacerbated cypermethrin-induced increase in oxidative stress and intrinsic apoptosis and reduction in expression of mitochondrial antioxidant proteins via inhibiting nuclear translocation of Nrf2. Additionally, cypermethrin-induced oxidative stress, mitochondrial impairment, and α-synuclein expression and aggregation were found to be suppressed by LRRK2 gene knockdown, by promoting Nrf2 nuclear translocation and expression of mitochondrial antioxidant proteins. Furthermore, Nrf2 activator, sulforaphane, ameliorated cypermethrin-induced mitochondrial impairment and oxidative stress and provided protection against dopaminergic neuronal death. The findings indicate that DJ-1 and LRRK2 independently alter Nrf2-mediated changes and a complex interplay among DJ-1, LRRK2, and Nrf2 exists in the regulation of mitochondrial function in cypermethrin-induced Parkinsonism.
氯菊酯会损害线粒体功能，诱导氧化还原失衡，并导致实验动物出现帕金森病。降解酶 1（DJ-1）基因的敲低会加剧氯菊酯介导的α-突触核蛋白过度表达和蛋白质的氧化改变，DJ-1 还被报道对于维持核因子红细胞 2 相关因子 2（Nrf2）的稳定性至关重要，可以保护细胞免受氧化损伤。另一种与帕金森病相关的蛋白质——富含亮氨酸重复激酶 2（LRRK2）也参与调节线粒体功能。然而，其潜在的分子机制仍不清楚。本研究旨在探讨 DJ-1、LRRK2 和 Nrf2 之间的相互作用在氯菊酯诱导的帕金森病中线粒体功能调节中的作用。在大鼠和/或人神经母细胞瘤细胞中，通过小干扰 RNA 介导的 DJ-1 和 LRRK2 基因敲低以及 Nrf2 的药理学激活，进行有无氯菊酯的实验。测定氧化应激、线粒体损伤和帕金森病的指标，以及α-突触核蛋白的表达、翻译后修饰和聚集。DJ-1 基因敲低通过抑制 Nrf2 的核转位，加剧了氯菊酯诱导的氧化应激和内在凋亡增加以及线粒体抗氧化蛋白表达减少。此外，LRRK2 基因敲低抑制了氯菊酯诱导的氧化应激、线粒体损伤和α-突触核蛋白表达和聚集，通过促进 Nrf2 的核转位和线粒体抗氧化蛋白的表达。此外，Nrf2 激活剂——萝卜硫素改善了氯菊酯诱导的线粒体损伤和氧化应激，并为多巴胺能神经元死亡提供了保护。研究结果表明，DJ-1 和 LRRK2 独立改变 Nrf2 介导的变化，DJ-1、LRRK2 和 Nrf2 之间存在复杂的相互作用，调节氯菊酯诱导的帕金森病中线粒体功能。
