Abstract：
Endoplasmic reticulum (ER) stress and oxidative stress (OS) are often related states in pathological conditions including Parkinson\'s disease (PD). This study investigates the role of anti-oxidant protein paraoxonase 2 (PON2) in ER stress and OS in PD, along with its regulatory molecule. PD was induced in C57BL/6 mice using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) treatment and in SH-SY5Y cells using 1-methyl-4-phenylpyridinium. PON2 was found to be poorly expressed in the substantia nigra pars compacta (SNc) of PD mice, and its overexpression improved motor coordination of mice. Through the evaluation of tyrosine hydroxylase, dopamine transporter, reactive oxygen species (ROS), and C/EBP homologous protein (CHOP) levels and neuronal loss in mice, as well as the examination of CHOP, glucose-regulated protein 94 (GRP94), GRP78, caspase-12, sarco/endoplasmic reticulum calcium ATPase 2, malondialdehyde, and superoxide dismutase levels in SH-SY5Y cells, we observed that PON2 overexpression mitigated ER stress, OS, and neuronal apoptosis both in vivo and in vitro. Forkhead box A1 (FOXA1) was identified as a transcription factor binding to the PON2 promoter to activate its transcription. Upregulation of FOXA1 similarly protected against neuronal loss by alleviating ER stress and OS, while the protective roles were abrogated by additional PON2 silencing. In conclusion, this study demonstrates that FOXA1-mediated transcription of PON2 alleviates ER stress and OS, ultimately reducing neuronal apoptosis in PD.
摘要：
内质网(ER)应激和氧化应激(OS)常与帕金森病(PD)等病理状态相关。本研究探讨了抗氧化蛋白对氧磷酶2（PON2）在PD的ER应激和OS中的作用，以及它的调控分子。使用1-甲基-4-苯基-1,2,3,6-四氢吡啶盐酸盐(MPTP)处理在C57BL/6小鼠中和使用1-甲基-4-苯基吡啶鎓在SH-SY5Y细胞中诱导PD。发现PON2在PD小鼠的黑质致密质（SNc）中表达不良，其过度表达改善了小鼠的运动协调性。通过对酪氨酸羟化酶的评价,多巴胺转运蛋白，活性氧（ROS），和C/EBP同源蛋白（CHOP）水平和小鼠的神经元丢失，以及CHOP的考试，葡萄糖调节蛋白94（GRP94），GRP78,caspase-12,sarco/内质网钙ATP酶2,丙二醛,和SH-SY5Y细胞中的超氧化物歧化酶水平，我们观察到PON2过表达减轻了ER应激，操作系统,体内和体外神经元凋亡。叉头盒A1(FOXA1)被鉴定为与PON2启动子结合以激活其转录的转录因子。通过减轻ER应激和OS，FOXA1的上调类似地保护免受神经元损失，而保护作用被额外的PON2沉默所废除。总之,这项研究表明FOXA1介导的PON2转录减轻了ER应激和OS，最终减少PD中的神经元凋亡。
