Singh Garima, Mittra Namrata, Singh Chetna
Systems Toxicology Group, Food, Drug & Chemical, Environment and Systems Toxicology (FEST) Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Post Box No. 80, Lucknow, 226001, Uttar Pradesh, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, Uttar Pradesh, India.
J Mol Neurosci. 2025 Feb 5;75(1):16. doi: 10.1007/s12031-024-02293-5.
Impairment in mitochondrial function and ubiquitin-proteasome system (UPS) and alpha-synuclein (α-Syn) aggregation are implicated in Zn-induced neurotoxicity. A link among these events leading to Zn-induced neurotoxicity is not yet properly deciphered. Therefore, the study intended to check the existence of a crosstalk between the mitochondria and UPS and its further link to α-Syn aggregation. The study also aimed to investigate the efficacy of tempol, a SOD mimetic and silymarin, a natural antioxidant, against Zn-induced alterations in animals and differentiated cells. Zn reduced the locomotor activity, dopamine content and tyrosine hydroxylase (TH) expression in the exposed animals. Zn augmented the levels of mitochondrial reactive oxygen species, α-Syn and protein-ubiquitin conjugates. Mitochondrial membrane potential, adenosine triphosphate (ATP) production, UPS-associated enzymatic activities and levels of UPS subunits (SUG-1 and β-5) were attenuated in Zn-exposed animals. While Zn augmented the expression of heat shock protein 110 (HSP110), peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) and Parkin translocation, the mitochondrial PTEN-induced kinase-1 (PINK-1) level was attenuated. In addition to tempol and silymarin, a mitochondrial permeability transition pore inhibitor, cyclosporine A, also alleviated the Zn-induced changes in animals. Similar trends in a few parameters were also observed in the differentiated human neuroblastoma SH-SY-5Y cells. Besides, UPS inhibitor, MG132, enhanced Zn-induced UPS impairment, protein aggregation and mitochondrial dysfunction in differentiated cells. These results suggest that mitochondrial dysfunction triggers UPS impairment or vice versa that elevates α-Syn aggregation and consequent neuronal death. Furthermore, tempol and silymarin ameliorate the mitochondrial and UPS impairments and α-Syn aggregation thereby providing protection from Zn-induced neurotoxicity.
线粒体功能、泛素 - 蛋白酶体系统（UPS）损伤以及α - 突触核蛋白（α - Syn）聚集与锌诱导的神经毒性有关。导致锌诱导神经毒性的这些事件之间的联系尚未得到恰当阐释。因此，本研究旨在检验线粒体与UPS之间是否存在相互作用及其与α - Syn聚集的进一步联系。该研究还旨在探究超氧化物歧化酶模拟物tempol和天然抗氧化剂水飞蓟素对锌诱导的动物和分化细胞变化的疗效。锌降低了暴露动物的运动活性、多巴胺含量和酪氨酸羟化酶（TH）表达。锌增加了线粒体活性氧、α - Syn和蛋白质 - 泛素缀合物的水平。锌暴露动物的线粒体膜电位、三磷酸腺苷（ATP）生成、UPS相关酶活性以及UPS亚基（SUG - 1和β - 5）水平均降低。虽然锌增加了热休克蛋白110（HSP110）、过氧化物酶体增殖物激活受体γ共激活因子 - 1α（PGC - 1α）的表达以及帕金蛋白易位，但线粒体PTEN诱导激酶 - 1（PINK - 1）水平降低。除了tempol和水飞蓟素外，线粒体通透性转换孔抑制剂环孢素A也减轻了锌诱导的动物变化。在分化的人神经母细胞瘤SH - SY - 5Y细胞中也观察到了一些参数的类似趋势。此外，UPS抑制剂MG132增强了锌诱导的分化细胞中UPS损伤、蛋白质聚集和线粒体功能障碍。这些结果表明，线粒体功能障碍引发UPS损伤，反之亦然，进而升高α - Syn聚集并导致神经元死亡。此外，tempol和水飞蓟素可改善线粒体和UPS损伤以及α - Syn聚集，从而提供对锌诱导神经毒性的保护作用。
