JMJD3 and SNAI2 synergistically protect against Parkinson’s disease by mediating the YAP/HIF1α signaling pathway in a mouse model

This study aimed to characterize the functional relevance and mechanistic basis of the histone demethylase Jumonji domain-containing protein-3 (JMJD3) in preserving dopaminergic neuron survival in Parkinson's disease (PD). Mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced lesions and MN9D dopaminergic neuronal cell lines exposed to 6-OHDA, respectively, were used to simulate in vivo and in vitro PD-like environments. PD-related genes with differential expressions were identified using RNA sequencing of hippocampal tissues collected from MPTP-lesioned mice. A specific lentiviral shRNA vector was used to investigate the effects of JMJD3 on neuron activities in vitro and PD-like phenotypes in vivo. JMJD3 was found to up-regulate the expression of Snail family transcriptional repressor 2 (SNAI2) through the inhibition of H3 on lysine 27 (H3K27me3) enrichment in the SNAI2 promoter region. As a result, the viability of 6-OHDA-exposed MN9D cells was stimulated, and cell apoptosis was diminished. Knockdown of SNAI2 decreased the expression of yes-associated protein (YAP) and HIF1α while also reducing the viability of 6-OHDA-exposed MN9D cells and increasing cell apoptosis. The in vivo experiments demonstrated that JMJD3 activated the SNAI2/YAP/HIF1α signaling pathway, inhibiting PD-like phenotypes in MPTP-lesioned mice. Thus, the findings provide evidence that JMJD3 inhibits the enrichment of H3K27me3 at the SNAI2 promoter, leading to the upregulation of SNAI2 expression and activation of the YAP/HIF1α signaling pathway, ultimately exerting a protective effect on PD mice. This finding suggests that targeting the JMJD3-SNAI2 pathway could be a promising therapeutic strategy for PD. Further in-depth studies are needed to elucidate the underlying mechanisms and identify potential downstream targets of this pathway.