Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
Department of Biochemistry, Nantong University College of Medicine, Nantong, China.
Neurotox Res. 2020 Oct;38(3):793-807. doi: 10.1007/s12640-020-00250-9. Epub 2020 Jul 2.
The present study investigated the effects of forced overexpression of Phox2a/2b, two transcription factors, in the locus coeruleus (LC) of aged rats on noradrenergic and dopaminergic phenotypes in brains. Results showed that a significant increase in Phox2a/2b mRNA levels in the LC region was paralleled by marked enhancement in expression of DBH and TH per se. Furthermore, similar increases in TH protein levels were observed in the substantial nigra and striatum, as well as in the hippocampus and frontal cortex. Overexpression of Phox2 genes also significantly increased BrdU-positive cells in the hippocampal dentate gyrus and NE levels in the striatum. Moreover, this manipulation significantly improved the cognition behavior. The in vitro experiments revealed that norepinephrine treatments may increase the transcription of TH gene through the epigenetic action on the TH promoter. The results indicate that Phox2 genes may play an important role in improving the function of the noradrenergic and dopaminergic neurons in aged animals, and regulation of Phox2 gene expression may have therapeutic utility in aging or disorders involving degeneration of noradrenergic neurons.
本研究探讨了在年老大鼠蓝斑（LC）中强制过表达两个转录因子 Phox2a/2b 对去甲肾上腺素能和多巴胺能表型的影响。结果表明，LC 区域 Phox2a/2b mRNA 水平的显著增加伴随着 DBH 和 TH 本身表达的显著增强。此外，在黑质和纹状体以及海马和额叶皮质中也观察到 TH 蛋白水平的相似增加。Phox2 基因的过表达也显著增加了海马齿状回中的 BrdU 阳性细胞和纹状体中的 NE 水平。此外，这种操作显著改善了认知行为。体外实验表明，去甲肾上腺素处理可能通过对 TH 启动子的表观遗传作用增加 TH 基因的转录。研究结果表明，Phox2 基因可能在改善年老动物去甲肾上腺素能和多巴胺能神经元的功能方面发挥重要作用，调节 Phox2 基因表达可能在涉及去甲肾上腺素能神经元变性的衰老或疾病中具有治疗作用。
