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Abstract：
Parkinson\'s disease (PD) is mainly characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and neuroinflammation mediated by overactivated microglia and astrocytes. NLRC5 (nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 5) has been reported to participate in various immune disorders, but its role in neurodegenerative diseases remains unclear. In the current study, we found that the expression of NLRC5 was increased in the nigrostriatal axis of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced PD, as well as in primary astrocytes, microglia and neurons exposed to different neurotoxic stimuli. In an acute MPTP-induced PD model, NLRC5 deficiency significantly reduced dopaminergic system degeneration and ameliorated motor deficits and striatal inflammation. Furthermore, we found that NLRC5 deficiency decreased the expression of the proinflammatory genes IL-1β, IL-6, TNF-α and COX2 in primary microglia and primary astrocytes treated with neuroinflammatory stimuli and reduced the inflammatory response in mixed glial cells in response to LPS treatment. Moreover, NLRC5 deficiency suppressed activation of the NF-κB and MAPK signaling pathways and enhanced the activation of AKT-GSK-3β and AMPK signaling in mixed glial cells. Furthermore, NLRC5 deficiency increased the survival of primary neurons treated with MPP+ or conditioned medium from LPS-stimulated mixed glial cells and promoted activation of the NF-κB and AKT signaling pathways. Moreover, the mRNA expression of NLRC5 was decreased in the blood of PD patients compared to healthy subjects. Therefore, we suggest that NLRC5 promotes neuroinflammation and dopaminergic degeneration in PD and may serve as a marker of glial activation.
摘要：
帕金森病（PD）的主要特征是黑质致密质（SNpc）中多巴胺能神经元的进行性变性和过度激活的小胶质细胞和星形胶质细胞介导的神经炎症。据报道，NLRC5（核苷酸结合寡聚化结构域样受体家族caspase募集结构域）参与各种免疫疾病，但其在神经退行性疾病中的作用尚不清楚。在目前的研究中,我们发现，NLRC5的表达在1-甲基-4-苯基-1,2,3,6-四氢吡啶盐酸盐（MPTP）诱导的PD小鼠的黑质纹状体轴中增加，以及在原代星形胶质细胞中，小胶质细胞和神经元暴露于不同的神经毒性刺激。在急性MPTP诱导的PD模型中,NLRC5缺乏可显着减少多巴胺能系统变性并改善运动缺陷和纹状体炎症。此外，我们发现NLRC5缺乏降低了促炎基因IL-1β的表达，用神经炎性刺激处理的原代小胶质细胞和原代星形胶质细胞中的IL-6，TNF-α和COX2，并减少了响应于LPS处理的混合神经胶质细胞中的炎症反应。此外，NLRC5缺陷抑制了NF-κB和MAPK信号通路的激活，并增强了混合胶质细胞中AKT-GSK-3β和AMPK信号的激活。此外，NLRC5缺陷增加了用MPP+或来自LPS刺激的混合神经胶质细胞的条件培养基处理的原代神经元的存活,并促进了NF-κB和AKT信号通路的激活。此外，与健康受试者相比，PD患者血液中NLRC5的mRNA表达降低。因此,我们建议NLRC5促进PD的神经炎症和多巴胺能变性,并可能作为神经胶质激活的标志.
