Abstract：
Forkhead box A1 (FOXA1), a member of the forkhead family of transcription factors, plays a crucial role in the development of various organ systems and exhibits neuroprotective properties. This study aims to investigate the effect of FOXA1 on Parkinson\'s disease (PD) and unravel the underlying mechanism. Transcriptome analysis of PD was conducted using three GEO datasets to identify aberrantly expressed genes. A mouse model of PD was generated by injecting neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), resulting in reduced FOXA1 expression. FOXA1 decline was also observed in 1-methyl-4-phenylpyridinium-treated SH-SY5Y cells. Artificial upregulation of FOXA1 improved motor abilities of mice according to rotarod and pole tests, and it mitigated tissue damage, cell loss, and neuronal damage in the mouse substantia nigra or in vitro. FOXA1 was found to bind to the neurofibromin 1 (NF1) promoter, thereby inducing its transcription and inactivating the mitogen-activated protein kinase (MAPK) signaling pathway. Further experimentation revealed that silencing NF1 in mice or SH-SY5Y cells counteracted the neuroprotective effects of FOXA1. In conclusion, this research suggests that FOXA1 activates NF1 transcription and inactivates the MAPK signaling pathway, ultimately ameliorating neuronal damage and motor disability in PD. The findings may offer novel ideas in the field of PD management.
摘要：
叉头箱A1(FOXA1),转录因子叉头家族的成员，在各种器官系统的发育中起着至关重要的作用，并具有神经保护特性。本研究旨在探讨FOXA1对帕金森病(PD)的治疗作用及其机制。使用三个GEO数据集进行PD的转录组分析以鉴定异常表达的基因。通过注射1-甲基-4-苯基-1,2,3,6-四氢吡啶盐酸盐（MPTP）产生PD的小鼠模型，导致FOXA1表达减少。在1-甲基-4-苯基吡啶鎓处理的SH-SY5Y细胞中也观察到FOXA1下降。根据旋转杆和极点测试，FOXA1的人工上调改善了小鼠的运动能力，它减轻了组织损伤，细胞损失，和小鼠黑质或体外的神经元损伤。发现FOXA1与神经纤维蛋白1（NF1）启动子结合，从而诱导其转录并使丝裂原活化蛋白激酶（MAPK）信号通路失活。进一步的实验表明，在小鼠或SH-SY5Y细胞中沉默NF1可以抵消FOXA1的神经保护作用。总之,这项研究表明，FOXA1激活NF1转录并使MAPK信号通路失活，最终改善PD的神经元损伤和运动障碍。这些发现可能为PD管理领域提供新的思路。
