miRNAs介导调控DDIT3基因表达在丙酮醛损伤记忆过程的作用探索

Role Exploration of the miRNAs-Mediated Regulation of DDIT3 Expression in the Methylglyoxal Induced Memory Impairment

摘要: 记忆损伤是一种神经退行性疾病相关的典型症状，然而记忆损伤的发生原因复杂，具体机制仍不明确。丙酮醛(MGO)作为糖代谢的中间产物被证实具有神经性毒性，我们研究发现MGO处理大鼠脑组织能够引起动物显著的记忆损伤。通过转录组筛选发现miR-96-5p以及miR-183-5p在MGO处理后表达水平显著降低。体外细胞实验表明miR-96-5p与miR-183-5p能够特异性靶向抑制DDIT3基因的蛋白CHOP表达水平，同时显著抑制促凋亡蛋白BAX以及PARP的表达水平，从而显著提升抗凋亡蛋白Bcl-2的表达水平。另外，体外研究发现转染miR-96-5p与miR-183-5p可显著降低MGO诱导的SH-SY5Y细胞的凋亡率。研究表明MGO引起特异记忆损伤跟miRNAs介导CHOP表达抑制相关，miR-96-5p/miR-183-5p具有改善MGO引起的细胞凋亡从而改善记忆损伤的应用潜力。尽管MGO损伤记忆的机制解析仍需更全面的研究，我们的研究结论为进一步理解记忆损伤病理机制以及开发基于miRNAs的治疗新方法奠定良好基础。

Abstract: Memory impairment is a typical symptom associated with neurodegenerative diseases; however, the causes of memory impairment are complex, and the specific mechanisms remain unclear. Methylglyoxal (MGO), an intermediate product of glucose metabolism, has been shown to possess neurotoxicity. Our study found that MGO treatment of rat brain tissue could cause significant memory impairment. Transcriptome screening revealed that the expression levels of miR-96-5p and miR-183-5p were significantly reduced after MGO treatment. Our vitro experiments showed that miR-96-5p and miR-183-5p can specifically target the DDIT3 gene and inhibit CHOP expression level, while significantly inhibiting the expression levels of pro-apoptotic proteins BAX and PARP, and significantly increasing the expression levels of anti-apoptotic protein Bcl-2. Additionally, our study revealed that transfection with miR-96-5p and miR-183-5p could significantly reduce MGO-induced SH-SY5Y cells’ apoptosis rate. Our studies indicate that MGO-induced specific memory impairment is associated with the sustained reduction in CHOP expression mediated by miRNAs, and miR-96-5p/miR-183-5p demonstrate potential for improving MGO-induced cell apoptosis and thereby mitigating memory impairment. Although the mechanisms underlying MGO-induced memory impairment require further comprehensive investigation, our findings lay a solid foundation for elucidating the pathological mechanisms of memory impairment and developing novel miRNA-based therapeutic approaches.