Ham Sangwoo, Kim Ji Hun, Kim Heejeong, Shin Jeong-Yong, Lee Yunjong
Department of Pharmacology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 16419 Suwon, Gyeonggi-do Republic of Korea.
Toxicol Res. 2022 Dec 8;39(2):191-199. doi: 10.1007/s43188-022-00157-x. eCollection 2023 Apr.
The E3 ubiquitin ligase parkin plays neuroprotective functions in the brain and the deficits of parkin's ligase function in Parkinson's disease (PD) is associated with reduced survival of dopaminergic neurons. Thus, compounds enhancing parkin expression have been developed as potential neuroprotective agents that prevent ongoing neurodegeneration in PD environments. Besides, iron chelators have been shown to have neuroprotective effects in diverse neurological disorders including PD. Although repression of iron accumulation and oxidative stress in brains has been implicated in their marked neuroprotective potential, molecular mechanisms of iron chelator's neuroprotective function are largely unexplored. Here, we show that the iron chelator deferasirox provides cytoprotection against oxidative stress through enhancing parkin expression under basal conditions. Parkin expression is required for cytoprotection against oxidative stress in SH-SY5Y cells with deferasirox treatment as confirmed by abolished deferasirox's cytoprotective effect after parkin knockdown by shRNA. Similar to the previously reported parkin inducing compound diaminodiphenyl sulfone, deferasirox-mediated parkin expression was induced by activation of the PERK-ATF4 pathway, which is associated with and stimulated by mild endoplasmic reticulum stress. The translational potential of deferasirox for PD treatment was further evaluated in cultured mouse dopaminergic neurons. There was a robust ATF4 activation and parkin expression in response to deferasirox treatment in dopaminergic neurons under basal conditions. Consequently, the enhanced parkin expression by deferasirox provided substantial neuroprotection against 6-hydroxydopamine-induced oxidative stress. Taken together, our study results revealed a novel mechanism through which an iron chelator, deferasirox induces neuroprotection. Since parkin function in the brain is compromised in PD and during aging, maintenance of parkin expression through the iron chelator treatment could be beneficial by increasing dopaminergic neuronal survival.
E3泛素连接酶帕金蛋白在大脑中发挥神经保护功能，而帕金森病（PD）中帕金蛋白连接酶功能的缺陷与多巴胺能神经元存活率降低有关。因此，已开发出增强帕金蛋白表达的化合物作为潜在的神经保护剂，以防止PD环境中正在进行的神经退行性变。此外，铁螯合剂已被证明在包括PD在内的多种神经系统疾病中具有神经保护作用。尽管大脑中铁积累和氧化应激的抑制与其显著的神经保护潜力有关，但铁螯合剂神经保护功能的分子机制在很大程度上尚未被探索。在这里，我们表明铁螯合剂地拉罗司在基础条件下通过增强帕金蛋白表达来提供针对氧化应激的细胞保护作用。用shRNA敲低帕金蛋白后，地拉罗司的细胞保护作用消失，这证实了在SH-SY5Y细胞中用其处理时，针对氧化应激的细胞保护作用需要帕金蛋白表达。与先前报道的诱导帕金蛋白的化合物二氨基二苯砜类似，地拉罗司介导的帕金蛋白表达是由PERK-ATF4途径的激活诱导的，该途径与轻度内质网应激相关并受其刺激。在培养的小鼠多巴胺能神经元中进一步评估了地拉罗司对PD治疗的转化潜力。在基础条件下，多巴胺能神经元对地拉罗司治疗有强烈的ATF4激活和帕金蛋白表达。因此，地拉罗司增强的帕金蛋白表达为6-羟基多巴胺诱导的氧化应激提供了实质性的神经保护。综上所述，我们的研究结果揭示了铁螯合剂地拉罗司诱导神经保护的新机制。由于PD和衰老过程中大脑中帕金蛋白的功能受损，通过铁螯合剂治疗维持帕金蛋白表达可能通过增加多巴胺能神经元存活率而有益。
