Dong Li, Gao Lianbo
Department of Neurology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
Hum Mol Genet. 2023 Oct 17;32(21):3040-3052. doi: 10.1093/hmg/ddad115.
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.
本研究旨在表征组蛋白去甲基化酶含jumonji结构域蛋白3（JMJD3）在帕金森病（PD）中维持多巴胺能神经元存活的功能相关性及机制基础。分别用1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导损伤的小鼠和暴露于6-羟基多巴胺（6-OHDA）的MN9D多巴胺能神经元细胞系来模拟体内和体外的PD样环境。通过对从MPTP损伤小鼠收集的海马组织进行RNA测序，鉴定出差异表达的PD相关基因。使用特异性慢病毒shRNA载体研究JMJD3对体外神经元活性和体内PD样表型的影响。研究发现，JMJD3通过抑制Snail家族转录抑制因子2（SNAI2）启动子区域赖氨酸27（H3K27me3）的组蛋白H3富集来上调SNAI2的表达。结果，暴露于6-OHDA的MN9D细胞的活力受到刺激，细胞凋亡减少。敲低SNAI2会降低Yes相关蛋白（YAP）和缺氧诱导因子1α（HIF1α）的表达，同时也会降低暴露于6-OHDA的MN9D细胞的活力并增加细胞凋亡。体内实验表明，JMJD3激活SNAI2/YAP/HIF1α信号通路，抑制MPTP损伤小鼠的PD样表型。因此，这些发现提供了证据，表明JMJD3抑制SNAI2启动子处H3K27me3的富集，导致SNAI2表达上调和YAP/HIF1α信号通路激活，最终对PD小鼠发挥保护作用。这一发现表明，靶向JMJD3-SNAI2通路可能是一种有前景的PD治疗策略。需要进一步深入研究以阐明其潜在机制并确定该通路潜在的下游靶点。
