脑内质网膜中压力诱导的CHOP激活介导了BDE-47诱导的认知功能障碍中的NLRP3炎症酶依赖性烧灭
Neurotoxicology
|February 19, 2026
概括
化二乙烯-47 (BDE-47) 通过诱导内分泌网膜 (ER) 应激和激活NLRP3炎症体,导致神经元热和认知缺陷,引起神经毒性.
科学领域:
- 神经科学是一个神经科学.
- 毒理学 毒理学 毒理学
- 细胞生物学 细胞生物学
背景情况:
- 细胞内膜网膜 (ER) 应激和NLRP3炎症酶激活与化二乙醇 (BDE) 的毒性有关.
- 对于ER压力和NLRP3炎症酶在BDE-47诱导的神经元灭和认知障碍中的特定作用尚未完全理解.
研究的目的:
- 为了研究ER压力和NLRP3炎症酶在BDE-47神经毒性的相互作用.
- 阐明BDE-47诱导的神经元灭和认知缺陷背后的机制.
主要方法:
- 在BDE-47治疗的小鼠海马和SH-SY5Y细胞中评估了ER压力标志物 (p-PERK,p-IRE1α,ATF6,CHOP) 和ER扩张.
- 使用ER压力抑制剂4-PBA和CHOPsiRNA来阻止ER压力和C.elegans.
- 给BDE-47暴露的小鼠使用ER应激抑制剂4-PBA和NLRP3炎症酶抑制剂MCC950.
主要成果:
- 暴露于BDE-47显著增加了ER压力标志物,并导致ER扩张.
- BDE-47诱导的CHOP上调调节激活了NLRP3炎症体,触发了神经元灭.
- 抑制ER压力或CHOP阻断了BDE-47诱导的烧灭.
- 在小鼠中,ER压力或NLRP3炎症酶抑制减轻了神经元损伤,突触功能障碍和认知缺陷.
结论:
- BDE-47神经毒性涉及ER压力介导的NLRP3炎症体的激活和随后的神经元灭.
- 针对ER压力和NLRP3炎症酶途径为BDE-47诱导的神经行为障碍提供了潜在的治疗策略.
相关概念视频
ER Retrieval Pathway
In the secretory pathway, vesicles transport proteins from one cellular compartment to another in forward transport to deliver the protein to its correct location. Occasionally, misfolded proteins and incorrect proteins escape their original compartments, and a retrieval pathway is used to return the escaped proteins to their original compartment.
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
The Unfolded Protein Response
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
Export of Misfolded Proteins out of the ER
After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
Regulation of the Unfolded Protein Response
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
The Intrinsic Apoptotic Pathway
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...


