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.
Keywords: Forkhead box A1; MAPK signaling pathway; Neurofibromin 1; Neuroprotection; Parkinson's disease.
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