在抑郁症大鼠模型中MiRNA-103-3p调控Rab10促进神经细胞自噬

doi:10.12122/j.issn.1673-4254.2024.07.11

南方医科大学学报 ›› 2024, Vol. 44 ›› Issue (7): 1315-1326.doi: 10.12122/j.issn.1673-4254.2024.07.11

• • 上一篇

在抑郁症大鼠模型中MiRNA-103-3p调控Rab10促进神经细胞自噬

张叶明¹^,²^,³(), 张袁祥¹^,²^,³, 沈学彬¹^,²^,³, 王国栋¹^,²^,³^,⁴(), 朱磊¹^,²^,³^,⁴()

^1.皖南医学院药学院，安徽芜湖 241002
^2.安徽省多糖药物工程技术研究中心，安徽芜湖 241002
^3.安徽省皖南地区植物药活性物质筛选与再评价工程实验室，安徽芜湖 241002
^4.安徽省代谢性疾病药物基础研究创新中心，安徽芜湖 241002

收稿日期:2024-04-25 出版日期:2024-07-20 发布日期:2024-07-25
通讯作者: 王国栋,朱磊 E-mail:zhangym@wnmc.edu.cn;wangguodong@wnmc.edu.cn;zhulei-6b110@163.com
作者简介:张叶明，副教授，E-mail: zhangym@wnmc.edu.cn
基金资助:
安徽省高等学校自然科学重点研究项目(KJ2021A0858)

MiRNA-103-3p promotes neural cell autophagy by activating Wnt/β-catenin signaling via targeting rab10 in a rat model of depression

Yeming ZHANG¹^,²^,³(), Yuanxiang ZHANG¹^,²^,³, Xuebin SHEN¹^,²^,³, Guodong WANG¹^,²^,³^,⁴(), Lei ZHU¹^,²^,³^,⁴()

^1.School of Pharmacy, Wannan Medical College, Wuhu 241002, China
^2.Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Wuhu, 241002, China
^3.Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Wuhu 241002, China
^4.Anhui Innovative Center for Drug Basic Research of Metabolic Diseases, Wuhu 241002, China

Received:2024-04-25 Online:2024-07-20 Published:2024-07-25
Contact: Guodong WANG, Lei ZHU E-mail:zhangym@wnmc.edu.cn;wangguodong@wnmc.edu.cn;zhulei-6b110@163.com

摘要/Abstract

摘要：

目的探讨与神经保护相关的基因Rab10在抑郁症体内外模型中发挥的功能和作用机制。方法选取36只大鼠作为慢性应激模型组（CUMS组），每只大鼠单笼饲养，进行6周慢性不可预测温和应激，另选取12只作为对照组。CUMS组大鼠完成6周CUMS刺激后，根据旷场实验数据和体质量分成3组（12只/组）：CUMS+生理盐水组、CUMS+AAV载体组和CUMS+AAV过表达Rab10组，CUMS+saline组大鼠侧脑室注射生理盐水；CUMS+AAV组大鼠侧脑室注射AAV空病毒载体；CUMS+AAV-oe-Rab10组大鼠侧脑室注射AAV过表达Rab10载体实现Rab10基因过表达，CUMS刺激在整个实验期间持续进行。对照组大鼠始终不进行任何刺激。利用大鼠行为学指标的变化评价大鼠抑郁状态。构建CORT诱导的PC12细胞模型，CCK-8法检测细胞活力。通过TargetScan数据库预测与Rab10相互作用的miRNA及miRNA结合位点，并结合双荧光素酶和RIP实验探究miRNA-103-3p与Rab10的相互作用。在CORT刺激的PC12细胞中过表达Rab10，或在转染miRNA-103-3p inhibitor基础上沉默Rab10，qRT-PCR法检测miRNA-103-3p和Rab10的表达水平；Western blotting检测细胞中Rab10、BDNF、CREB、p62、Beclin-1、Wnt3a、Gsk3β、磷酸化（p）-Gsk3β和β-catenin的蛋白含量。结果病毒过表达Rab10后明显改善CUMS大鼠行为学指标（P<0.05）。qRT-PCR和Western blotting证实Rab10基因在CUMS大鼠海马与CORT诱导的PC12细胞中表达下调（P<0.05）。生物信息学结合双荧光素酶和RIP实验证实miRNA-103-3p靶向Rab10（P<0.05）。过表达Rab10或沉默miRNA-103-3p激活了Wnt/β-catenin信号通路，上调BDNF、CREB和Beclin-1的含量，下调p62蛋白的表达（P<0.05）；下调miRNA-103-3p的基础上沉默Rab10逆转了miRNA-103-3p的作用（P<0.05）。结论 miRNA103-3p靶向Rab10激活Wnt/β-catenin信号通路，改善神经细胞的可塑性，促进细胞自噬，从而对抗CORT诱导的PC12细胞损伤。

关键词: Rab10, miRNA-103-3p, 神经可塑性, 自噬, 抑郁症

Abstract:

Objective To explore the neuroprotective role of Rab10 gene in depression and the mechanism mediating its effect. Methods Forty-eight male SD rats were randomized into a control group and 3 chronic unpredictable mild stress (CUMS) groups (n=12). The rats in the latter 3 groups were subjected to injections of normal saline, an adeno-associated viral (AAV) vector, or a Rab10-overexpressing AAV vector in the lateral ventricle after CUMS modeling. The depressive behavioral changes of the rats were assessed using behavioral tests. The TargetScan database was used to predict the miRNA interacting with Rab10 and the binding sites. The interaction between miRNA-103-3p and Rab10 was investigated using dual-luciferase and radioimmunoprecipitation (RIP) assay. The effect of corticosterone treatment on PC12 cell viability was assessed with CCK-8 assay. In corticosterone-stimulated PC12 cells, the changes in BDNF, CREB, p62, Beclin-1, Wnt3a, Gsk3β, phosphorylated (p)-Gsk3β, and β-catenin protein expressions following transfection with the Rab10-overexpressing AAV vector and a miRNA-103-3p inhibitor, alone or in combination, were analyzed using qRT-PCR and Western blotting. Results Injection of Rab10-overexpressing AVV vector into the lateral ventricle significantly improved depressive behaviors of CUMS rats. The mRNA and proteins expression of Rab10 were significantly down-regulated in the hippocampus of CUMS rats and in corticosterone-stimulated PC12 cells. Bioinformatics analysis and the results of double luciferase and RIP experiments confirmed the targeting relationship between miRNA-103-3p and Rab10. In PC12 cells, overexpression of Rab10 or silencing miRNA-103-3p activated the Wnt/β-catenin signaling pathway, up-regulated the expressions of BDNF, CREB and Beclin-1, and down-regulated the expression of p62 protein; silencing Rab10 obviously blocked the effect of miRNA-103-3p inhibitor. Conclusion In mouse models of depression, miRNA-103-3p activates Wnt/β-catenin signaling via targeting rab10 to improve neural plasticity and promotes neural cell autophagy.

Key words: Rab10, miRNA-103-3p, neural plasticity, autophagy, depression

张叶明, 张袁祥, 沈学彬, 王国栋, 朱磊. 在抑郁症大鼠模型中MiRNA-103-3p调控Rab10促进神经细胞自噬[J]. 南方医科大学学报, 2024, 44(7): 1315-1326.

Yeming ZHANG, Yuanxiang ZHANG, Xuebin SHEN, Guodong WANG, Lei ZHU. MiRNA-103-3p promotes neural cell autophagy by activating Wnt/β-catenin signaling via targeting rab10 in a rat model of depression[J]. Journal of Southern Medical University, 2024, 44(7): 1315-1326.

图/表 11

图1 动物实验分组情况及流程图

Fig.1 Grouping and flow chart of the animal experiment.

表1 qRT-PCR的引物序列

Tab.1 Primer sequences for qRT-PCR

Gene	Primer sequence (5'-3')
Rab10	F: GCTGAAGACATCCTCCGAAAGACC
Rab10	R: CCGTCACGCCTCCTCCACTG
miRNA-103-3p	F: GAGCAGCATTGTACAG
miRNA-103-3p	R: GTGCAGGGTCCGAGGT
GAPDH	F: ACAACTTTGGTATCGTGGAAGG
GAPDH	R: GCCATCACGCCACAGTTTC
U6	F: GCTTCGGCAGCACATATACTAAAAT
U6	R: CGCTTCACGAATTTGCGTGTCAT

图2 CUMS刺激6周后大鼠的行为学变化

Fig.2 Behavioral changes of rats after 6 weeks of CUMS stimulation. A: Changes of body weight of rats during CUMS. B: Effect of CUMS on total distance of the rats in open field test. C: Effect of CUMS on rearing times of the rats in open field test. D: Effect of CUMS on the number of zone crossing in open field experiment. E: Effect of CUMS on sucrose preference in each group. F: Effect of CUMS on immovability time during forced swimming test. *P<0.05 vs Control.

图3 过表达Rab10减轻CUMS诱导的大鼠抑郁样行为

Fig.3 Overexpression of Rab10 attenuates CUMS-induced depression-like behaviors in rats. A: Changes of body weight of the rats after overexpression of Rab10. B: Changes of total distance of the rats in open field test after overexpression of Rab10. C: Changes of rearing times in open field test after Rab10 overexpression. D: Changes of the number of zone crossing in open field experiment after Rab10 overexpression. E: Changes of sucrose preference in rats after Rab10 overexpression. F: Changes of immovability time of the rats after Rab10 overexpression. *P<0.05 vs. sham; #P<0.05 vs CUMS+AAV-NC.

图4 CORT刺激PC12细胞建立抑郁症体外模型并检测细胞与海马中Rab10的表达

Fig.4 Expression of Rab10 in PC12 cells after CORT stimulation and in the hippocampus of CUMS mice. A: Detection of Rab10 expression in rat hippocampus by qRT-PCR. B: Protein levels of Rab10 in the hippocampus detected using Western blotting. C: Relative Rab10 protein expression levels. D: CCK-8 experiment for determining optimal concentration of CORT. E: qRT-PCR for detecting the expression of Rab10 in PC12 cells stimulated by CORT. F, G: Protein levels of Rab10 in the cells detected using Western blotting. H, I: Protein levels of Rab10 in PC12 cells detected using Western blotting. *P<0.05 vs Sham, Control, CORT+oe-NC; #P<0.05 vs CUMS+AAV.

图5 Western blotting检测细胞中神经可塑性和自噬相关蛋白的变化

Fig.5 Detection of neuroplasticity and autophagy-related proteins in PC12 cells by Western blotting. A: Protein levels of BDNF, CREB, P62 and Beclin-1 in PC12 cells detected using Western blotting. B-E: Relative protein expression levels of BDNF (B), CREB (C), P62 (D), and Beclin-1 (E). *P<0.05 vs Control; #P<0.05 vs CORT+oe-NC.

图6 Western blotting确定细胞中过表达Rab10对Wnt/β-catenin信号通路的影响

Fig.6 Western blotting for assessing the effect of Rab10 overexpression on Wnt/β-catenin signaling pathway. A: Protein levels of Wnt3a, GSK3β, p-GSK3β and β-catenin in PC12 cells detected using Western blotting. B-D: Relative protein expression levels of Wnt3a, p-GSK3β/GSK3β and β-catenin, respectively. *P<0.05 vs Control; #P<0.05 vs CORT+oe-NC.

图7 验证miRNA-103-3p与Rab10之间的相互作用

Fig.7 Verification of the interaction between miRNA-103-3p and Rab10. A: TargetScan database showing the binding site of miRNA-103-3p for targeting Rab10. B: qRT-PCR for verifying the expression of miRNA-103-3p in the hippocampus of CUMS mice. C,D: Double luciferase reporter gene experiment confirms the interaction between miRNA-103-3p and Rab10. E: Interaction between miRNA-103-3p and Rab10 detected by Ago2 RIP experiment. *P<0.05 vs Control, miR-NC, anti-NC.

图8 miRNA-103-3p对Rab10表达水平的影响

Fig.8 Effect of miRNA-103-3p on Rab10 expression level. A: qRT-PCR for detecting miRNA-103-3p expression in PC12 cells induced by CORT. B: qRT-PCR for verifying interference efficiency of miRNA-103-3p in PC12 cells induced by CORT. C, D: Protein levels of Rab10 in the PC12 cells detected using Western blotting. E, F: Protein levels of Rab10 in PC12 cells with Rab10 knockdown detected using Western blotting. *P<0.05 vs Control, CORT+sh-NC; #P<0.05 vs CORT +inhibitor-NC.

图9 通过Western blotting测定miRNA-103-3p调控Rab10对细胞中神经可塑性和自噬相关蛋白表达的影响

Fig.9 Effects of miRNA-103-3p-mediated Rab10 regulation on neuroplasticity and autophagy-related protein expression in PC12 cells detected by Western blotting. A: Protein levels of BDNF, CREB, P62 and Beclin-1 in PC12 cells detected using Western blotting. B-E: Relative protein expression levels of BDNF, CREB, P62 and Beclin-1, respectively. *P<0.05 vs Control; #P<0.05 vs CORT+inhibitor-NC; &P<0.05 vs CORT+miRNA-103-3p inhibitor+sh-NC.

图10 通过Western blotting确定miRNA-103-3p调控Rab10对细胞中Wnt /β-catenin信号通路相关蛋白表达的影响

Fig.10 Western blotting for analyzing the effect of miRNA-103-3p on expressions of Wnt/β-catenin signaling pathway-related proteins in PC12 cells. A: Protein levels of Wnt3a, GSK3β, p-GSK3β and β-catenin in the cells detected using Western blotting. B-D: Relative protein expression levels of Wnt3a, GSK3β, p-GSK3β and β-catenin, respectively. *P<0.05 vs Control; #P<0.05 vs CORT+inhibitor-NC; &P<0.05 vs CORT+miRNA-103-3p inhibitor+sh-NC.

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在抑郁症大鼠模型中MiRNA-103-3p调控Rab10促进神经细胞自噬

MiRNA-103-3p promotes neural cell autophagy by activating Wnt/β-catenin signaling via targeting rab10 in a rat model of depression

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