Wnt-3a improves functional recovery through autophagy activation via inhibiting the mTOR signaling pathway after spinal cord injury
Wnt-3a improves functional recovery through autophagy activation via inhibiting the mTOR signaling pathway after spinal cord injury
复制标题
Wnt-3a 通过抑制脊髓损伤后的 mTOR 信号通路来激活自噬，从而改善功能恢复
DOI：
10.1016/j.neulet.2020.135305
复制
发表时间：
2020-10-15
影响因子：
2.5
通讯作者：
Dang, Xiaoqian
中科院分区：
文献类型：
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作者：
Gao, Kai;Niu, Jianbing;Dang, Xiaoqian
关于wnt-3a对脊髓损伤后运动神经功能的影响及其具体的分子机制尚不清楚。本研究表明，经wnt-3a处理后，caspase-3、cas-pases-9和硫酸软骨素蛋白聚糖（CSPG）蛋白的表达水平以及转移酶UTP缺口末端标记（TUNEL）阳性神经元的数量比例均下调。尼氏染色和HE染色结果显示，wnt-3a明显减少脊髓前角运动神经元的丢失，促进损伤脊髓组织的修复。上述因素为脊髓损伤后运动神经功能的恢复提供了良好的微环境。为阐明wnt-3a对SCI神经保护作用的分子机制，本研究发现，体内外实验wnt-3a均能显著提高SCI后脊髓神经元Beclin-1和轻链（LC）3-II/I的表达水平，而MHY-1485激活mTOR信号通路后，wnt-3a的作用被抑制。此外，wnt-3a可抑制p70 S6 K磷酸化水平，而上调p70 S6 K蛋白水平，表明wnt-3a可通过抑制mTOR信号通路激活脊髓损伤后神经元自噬。为了进一步验证wnt-3a的神经保护作用与自噬的相关性，我们发现wnt-3a和MHY-1485联合处理大鼠和脊髓神经元后，wnt-3a对SCI的神经保护作用明显受到抑制。这项研究首次报道了wnt-3a通过抑制mTOR信号通路，通过自噬激活改善SCI后的功能恢复。
Little is known about the effect of wnt-3a on motor nerve function and its specific molecular mechanisms after spinal cord injury (SCI). This study demonstrates that the downregulated expression levels of caspases-3, cas-pases-9 and chondroitin sulfate proteoglycan (CSPG) proteins and number of proportion of transferase UTP nick end labeling (TUNEL)-positive neurons by wnt-3a treatment. Then, Nissl and hematoxylin-eosin (HE) staining showed that wnt-3a significantly reduced the loss of spinal anterior horn motor neurons and promoted repair injured spinal cord tissues after SCI. The above factors constructed a favorable microenvironment for the recovery of motor nerve function after SCI. To elucidate the molecular mechanism of neuroprotection of wnt-3a on SCI, the study showed that the expression levels of Beclin-1 and light chain (LC)3-II/I in spinal cord neurons were significantly improved by wnt-3a after SCI in vitro and vivo experiments, while the effect of wnt-3a was inhibited after mechanistic target of rapamycin (mTOR) signaling pathway being activated by MHY-1485. Besides, the level of p70S6K phosphorylation was inhibited by wnt-3a treatment, on the contrary, the level of p70S6K protein was elevated by wnt-3a, indicating that wnt-3a significantly activated neuronal autophagy by inhibiting mTOR signaling pathway after SCI. To further verify the correlation between neuroprotection of wnt-3a and autophagy, we found that after the rats and spinal cord neurons were combined treatment with wnt-3a and MHY-1485, the neuroprotection of wnt-3a on SCI was significantly inhibited. This study is the first to report that wnt-3a improves functional recovery through autophagy activation via inhibiting the mTOR signaling pathway after SCI.