Microglia activation induced neuroinflammation closely relates with the development of Parkinson disease. Autophagy regulates many biological processes,but the role in microglial activation and the development of Park...Microglia activation induced neuroinflammation closely relates with the development of Parkinson disease. Autophagy regulates many biological processes,but the role in microglial activation and the development of Parkinson disease is not clear. In this study,we show that loss of microglial Atg5 cause neuroinflammation and motor and cognitive learning impairment in mice,with accumulation of α-synuclein and decrease of dopamine levels in the striatum. Inhibition of autophagy aggravates the activation of NLRP3 inflammasome via PDE10a-cAMP signaling in microglia. Furthermore,the downstream cytokine IL-1 increases Mif levels in a transcriptional dependent manner. Interestingly,Mif levels are significantly elevated in Parkinson disease patients. Taken together,our results reveal a protective role of autophagy in microglial activation-driven Parkinson disease,thus providing a potential targets for the clinical treatment.展开更多
目的:通过生物信息学方法分析阿尔茨海默病(Alzheimer disease,AD)中与星形胶质细胞相关的糖代谢通路,为揭示AD患者的星形胶质细胞在大脑中的糖代谢过程提供理论基础。方法:首先根据细胞特异性表达基因将AD患者和健康人脑组织单细胞转...目的:通过生物信息学方法分析阿尔茨海默病(Alzheimer disease,AD)中与星形胶质细胞相关的糖代谢通路,为揭示AD患者的星形胶质细胞在大脑中的糖代谢过程提供理论基础。方法:首先根据细胞特异性表达基因将AD患者和健康人脑组织单细胞转录组学测序结果进行降维分析,再根据星形胶质细胞不同亚型的基因表达特征进行细胞分群,对星形胶质细胞差异表达基因进行基因注释(Gene Ontology.GO)、信号通路分析(Kyoto Encyclopedia of Genes and Genomes,KEGG)以及基因集富集分析(Gene Set Enrichment Analysis,GSEA),采用转录调控网络分析与AD的星形胶质细胞相关的转录辅助因子。结果:所有细胞降维分析结果显示AD患者脑内星形胶质细胞和兴奋性神经元数量显著减少;星形胶质细胞降维分析结果显示其可以被进一步分为6个亚群,其中在AD患者中减少的星形胶质细胞主要为RASGEF1B^(+)SLC26A3^(+)亚群和NRGN^(+)CALM1^(+)亚群;GO分析结果显示AD患者与健康对照星形胶质细胞差异表达基因主要与轴突发生、神经元的迁移、胶质细胞分化、体内锌离子稳态、突触传递的正调控、血管运输有关。KEGG结果显示,上述差异基因主要与PI3K-Akt信号通路、AMPK信号通路、钙信号通路有关。GSEA分析结果显示,AD患者差异基因在糖酵解/糖异生通路中得到富集,其中丙酮酸激酶PKM、PFKL、ACSS1、乳酸脱氢酶LDHB在AD患者星形胶质细胞中下调。转录调控网络分析结果显示,星形胶质细胞中差异表达转录辅助因子有5个,其中PKM、SOX2、SOX9在AD患者星形胶质细胞中下调。SREBF1和BCL6在AD患者星形胶质细胞中上调。结论:AD患者脑内兴奋性神经元和星形胶质细胞数量降低,以及星形胶质细胞糖酵解相关基因下调。结合星形胶质细胞作为神经元的主要乳酸供应细胞,其数量减少和糖酵解能力减低提示星形胶质细胞供能不足可能是AD发生的机制之一。展开更多
文摘Microglia activation induced neuroinflammation closely relates with the development of Parkinson disease. Autophagy regulates many biological processes,but the role in microglial activation and the development of Parkinson disease is not clear. In this study,we show that loss of microglial Atg5 cause neuroinflammation and motor and cognitive learning impairment in mice,with accumulation of α-synuclein and decrease of dopamine levels in the striatum. Inhibition of autophagy aggravates the activation of NLRP3 inflammasome via PDE10a-cAMP signaling in microglia. Furthermore,the downstream cytokine IL-1 increases Mif levels in a transcriptional dependent manner. Interestingly,Mif levels are significantly elevated in Parkinson disease patients. Taken together,our results reveal a protective role of autophagy in microglial activation-driven Parkinson disease,thus providing a potential targets for the clinical treatment.
文摘目的:通过生物信息学方法分析阿尔茨海默病(Alzheimer disease,AD)中与星形胶质细胞相关的糖代谢通路,为揭示AD患者的星形胶质细胞在大脑中的糖代谢过程提供理论基础。方法:首先根据细胞特异性表达基因将AD患者和健康人脑组织单细胞转录组学测序结果进行降维分析,再根据星形胶质细胞不同亚型的基因表达特征进行细胞分群,对星形胶质细胞差异表达基因进行基因注释(Gene Ontology.GO)、信号通路分析(Kyoto Encyclopedia of Genes and Genomes,KEGG)以及基因集富集分析(Gene Set Enrichment Analysis,GSEA),采用转录调控网络分析与AD的星形胶质细胞相关的转录辅助因子。结果:所有细胞降维分析结果显示AD患者脑内星形胶质细胞和兴奋性神经元数量显著减少;星形胶质细胞降维分析结果显示其可以被进一步分为6个亚群,其中在AD患者中减少的星形胶质细胞主要为RASGEF1B^(+)SLC26A3^(+)亚群和NRGN^(+)CALM1^(+)亚群;GO分析结果显示AD患者与健康对照星形胶质细胞差异表达基因主要与轴突发生、神经元的迁移、胶质细胞分化、体内锌离子稳态、突触传递的正调控、血管运输有关。KEGG结果显示,上述差异基因主要与PI3K-Akt信号通路、AMPK信号通路、钙信号通路有关。GSEA分析结果显示,AD患者差异基因在糖酵解/糖异生通路中得到富集,其中丙酮酸激酶PKM、PFKL、ACSS1、乳酸脱氢酶LDHB在AD患者星形胶质细胞中下调。转录调控网络分析结果显示,星形胶质细胞中差异表达转录辅助因子有5个,其中PKM、SOX2、SOX9在AD患者星形胶质细胞中下调。SREBF1和BCL6在AD患者星形胶质细胞中上调。结论:AD患者脑内兴奋性神经元和星形胶质细胞数量降低,以及星形胶质细胞糖酵解相关基因下调。结合星形胶质细胞作为神经元的主要乳酸供应细胞,其数量减少和糖酵解能力减低提示星形胶质细胞供能不足可能是AD发生的机制之一。
