PDF(Pubmed)
Abstract：
Hippocampal neural stem/progenitor cells (NSPCs) are highly vulnerable to different stress stimuli, resulting in adult neurogenesis decline and eventual cognitive defects. Our previous study demonstrated that NOD-like receptor family pyrin domain-containing 6 (Nlrp6) highly expressed in NSPCs played a critical role in sustaining hippocampal neurogenesis to resist stress-induced depression, but the underlying mechnistms are still unclear. Here, we found that Nlrp6 depletion led to cognitive defects and hippocampal NSPC loss in mice. RNA-sequencing analysis of the primary NSPCs revealed that Nlrp6 deficiency altered gene expression profiles of mitochondrial energy generation and ferroptotic process. Upon siNlrp6 transfection, as well as corticosterone (CORT) exposure, downregulation of Nlrp6 suppressed retinoic acid-inducible gene I (RIG-1)/mitochondrial antiviral signaling proteins (MAVS)-mediated autophagy, but drove NSPC ferroptotic death. More interesting, short chain fatty acids (SCFAs) upregulated Nlrp6 expression and promoted RIG-1/MAVS-mediated mitophagy, preventing CORT-induced NSPC ferroptosis. Our study further demonstrates that Nlrp6 should be a sensor for RIG-1/MAVS-mediated mitophagy and play a critical role in maintain mitochondrial homeostasis of hippocampal NSPCs. These results suggests that Nlrp6 should be a potential drug target to combat neurodegenerative diseases relative with chronic stress.
摘要：
海马神经干/祖细胞(NSPCs)极易受到不同的应激刺激,导致成人神经发生衰退和最终的认知缺陷。我们先前的研究表明，在NSPCs中高度表达的含NOD样受体家族pyrin结构域6（Nlrp6）在维持海马神经发生以抵抗应激诱导的抑郁症中起着关键作用。但是潜在的机制仍然不清楚。这里,我们发现Nlrp6缺失导致小鼠认知缺陷和海马NSPC缺失。主要NSPC的RNA测序分析表明，Nlrp6缺陷改变了线粒体能量产生和铁过程的基因表达谱。在siNlrp6转染后，以及皮质酮（CORT）暴露，Nlrp6下调抑制维甲酸诱导基因I（RIG-1）/线粒体抗病毒信号蛋白（MAVS）介导的自噬，但导致NSPC铁性死亡。更有趣,短链脂肪酸（SCFA）上调Nlrp6表达并促进RIG-1/MAVS介导的线粒体自噬，防止CORT诱导的NSPC铁凋亡。我们的研究进一步表明，Nlrp6应该是RIG-1/MAVS介导的线粒体自噬的传感器，并在维持海马NSPCs的线粒体稳态中起关键作用。这些结果表明,Nlrp6应该是对抗与慢性应激相关的神经退行性疾病的潜在药物靶标。
