中国神经再生研究(英文版) ›› 2015, Vol. 10 ›› Issue (8): 1286-1291.doi: 10.4103/1673-5374.162763

• 原著:退行性病与再生 • 上一篇    下一篇

E3泛素连接酶1可能成为帕金森病治疗的新靶点?

  

  • 收稿日期:2015-06-09 出版日期:2015-08-24 发布日期:2015-08-24
  • 基金资助:

    中国博士后科学基金(1630),江苏省自然科学基金(bk2011402),江苏省博士后科研项目(1301174c),江苏省卫生厅(h201361)

The E3 ubiquitin ligase seven in absentia homolog 1 may be a potential new therapeutic target for Parkinson’s disease

Zeng-lin Cai1,  Jing Xu1, Shou-ru Xue2, Yuan-yuan Liu2, Yong-jin Zhang1, Xin-zhi Zhang1, Xuan Wang1, Fang-ping Wu1, Xiao-min Li1   

  1. 1 Department of Neurology, Affiliated Lianyungang Hospital of Xuzhou Medical College, Lianyungang, Jiangsu Province, China
    2 Department of Neurology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China  
  • Received:2015-06-09 Online:2015-08-24 Published:2015-08-24
  • Contact: Zeng-lin Cai, M.D., Jing Xu, Ph.D. or hou-ru Xue, M.D., caizengling@hotmail.com, 369610503@qq.com or xueshouru@suda.edu.cn.
  • Supported by:

    This study was supported by the China Postdoctoral Science Foundation, No. 1630; the Natural Science Foundation of Jiangsu Province in China, No. BK2011402; the Jiangsu Province Postdoctoral Research Foundation in China, No. 1301174C; the Jiangsu Province Health Department Foundation in China, No. H201361.

摘要:

课题希望深入探讨和揭示E3泛素连接酶1在α-synuclein降解通路中的作用。发现雷帕霉素和E3泛素连接酶1抗体处理PC12细胞可改善其活性的应激状态。经MPP+处理PC12细胞后可增加细胞中α-synuclein、泛素激活酶-E1蛋白和E3泛素连接酶1蛋白的表达,但自噬活性的金标准蛋白-LC3-Ⅱ未见明显表达。经MPP+处理PC12细胞后可增加细胞中α-synuclein、LC3-Ⅱ、E1和SIAH-1的mRNA表达,而抗E3泛素连接酶1抗体处理细胞后细胞中α-synuclein、LC3-Ⅱ、E3泛素连接酶1的mRNA表达显著降低,E1显著增强;经MPP+和雷帕霉素联合处理细胞,可降低细胞中E3泛素连接酶1和α-synuclein蛋白表达;E3泛素连接酶1抗体单独处理可显著降低PC12细胞中α-synuclein的免疫阳性反应,而α-synuclein和LC3在细胞内失去共定位。结果表明,E3泛素连接酶1降低了α-synuclein抗体的单泛素化和聚集,并有效地促进其通过泛素蛋白酶体系统通路降解,可能成为帕金森病未来治疗的新靶点。

关键词: 神经再生, 神经退行性变, 帕金森病, 自噬, 泛素蛋白酶体系统, E3泛素连接酶1, MPP+, 雷帕霉素

Abstract:

In this study, we investigated the effect of an antibody against E3 ubiquitin ligase seven in absentia homolog 1 (SIAH-1) in PC12 cells. 1-Methyl-4-phenylpyridinium (MPP+) treatment increased α-synuclein, E1 and SIAH-1 protein levels in PC12 cells, and it reduced cell viability; however, there was no significant change in light chain 3 expression. Treatment with an SIAH-1 antibody decreased mRNA expression levels of α-synuclein, light chain 3 and SIAH-1, but increased E1 mRNA expression. It also increased cell viability. Combined treatment with MPP+ and rapamycin reduced SIAH-1 and α-synuclein levels. Treatment with SIAH-1 antibody alone diminished α-synuclein immunoreactivity in PC12 cells, and reduced the colocalization of α-synuclein and light chain 3. These findings suggest that the SIAH-1 antibody reduces the monoubiquitination and aggregation of α-synuclein, promoting its degradation by the ubiquitin-proteasome pathway. Consequently, SIAH-1 may be a potential new therapeutic target for Parkinson’s disease.

Key words: nerve regeneration, neurodegeneration, Parkinson’s disease, ubiquitin-proteasome system, autophagy, E3 ubiquitin ligase seven in absentia homolog 1, 1-methyl-4-phenylpyridinium, rapamycin, neural regeneration