中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (7): 1609-1616.doi: 10.4103/1673-5374.330621

• 原著:退行性病与再生 • 上一篇    下一篇

磷酸肌醇-3-激酶调节亚基4调节自噬参与肌萎缩侧索硬化的发生和发展

  

  • 出版日期:2022-07-15 发布日期:2022-01-18
  • 基金资助:
    国家自然科学基金项目(30560042,81160161,81360198);江西省教育厅项目(GJJ170021);江西省科技厅项目([2014]-47, 2010462BBG,20171BAB215022,20192BAB205043);江西省卫健委项目(20181019)

Phosphoinositide-3-kinase regulatory subunit 4 participates in the occurrence and development of amyotrophic lateral sclerosis by regulating autophagy

Yue Liu#, Cai-Hui Wei#, Cheng Li#, Wen-Zhi Chen#, Yu Zhu, Ren-Shi Xu*   

  1. Department of Neurology, First Affiliated Hospital of Nanchang Medical College, Jiangxi Provincial People’s Hospital, Affiliated People’s Hospital of Nanchang University, Nanchang, Jiangxi Province, China
  • Online:2022-07-15 Published:2022-01-18
  • Contact: Ren-Shi Xu, PhD, xurenshi@nuc.edu.cn.
  • Supported by:
    The study was supported by the National Natural Science Foundation of China (Nos. 30560042, 81160161 and 81360198), Education Department of Jiangxi Province (No. GJJ170021), Jiangxi Provincial Department of Science and Technology (Nos. [2014]-47, 20142BBG70062, 20171BAB215022, 20192BAB205043), and Health Commission of Jiangxi Province (No. 20181019) (all to RSX).

摘要:

肌萎缩侧索硬化可能与多种蛋白异常表达有关。作者既往研究已发现肌萎缩侧索硬化小鼠磷酸肌醇-3-激酶调节亚基4表达降低。但其在肌萎缩侧索硬化发病中的作用尚不可知。此次实验首先发现经磷酸肌醇-3-激酶调节亚基4小干扰RNA转染后,PC12细胞中磷酸肌醇-3-激酶调节亚基4和自噬相关蛋白p62和LC3的表达显著降低。体内实验也发现,磷酸肌醇-3-激酶调节亚基4蛋白广泛表达于成年小鼠颈、胸、腰脊髓节段的前角、后角和中央管及其周围。磷酸肌醇-3-激酶调节亚基4主要在神经元中表达。磷酸肌醇-3-激酶调节亚基4和p62的表达在肌萎缩侧索硬化发病前和/或发病期显著降低,但在进展期显著升高。LC3的表达在肌萎缩侧索硬化病程中无明显变化。结果表明磷酸肌醇-3-激酶调节亚基4可能通过自噬调节参与预防肌萎缩侧索硬化的进展。实验于2020年3月26日经江西省人民医院、南昌大学附属人民医院动物伦理委员会批准(批准号2020025)。

https://orcid.org/0000-0003-0313-3434 (Ren-Shi Xu)

关键词: 肌萎缩侧索硬化, 磷酸肌醇-3-激酶调节亚基4, 自噬, p62, LC3, PC12细胞, Tg(SOD1*G93A)1Gur小鼠, 脊髓

Abstract: The development of amyotrophic lateral sclerosis (ALS) may be related to the abnormal alterations of multiple proteins. Our previous study revealed that the expression of phosphoinositide-3-kinase regulatory subunit 4 (PIK3R4) was decreased in ALS. However, the role of PIK3R4 in ALS pathogenesis remains unknown. This study was the first to find that transfection of PC12 cells with small interfering RNA against the PIK3R4 gene significantly decreased the expression levels of PIK3R4 and the autophagy-related proteins p62 and LC3. Additionally, in vivo experiments revealed that the PIK3R4 protein was extensively expressed in the anterior horn, posterior horn, central canal, and areas surrounding the central canal in cervical, thoracic, and lumbar segments of the spinal cord in adult mice. PIK3R4 protein was mainly expressed in the neurons within the spinal lumbar segments. PIK3R4 and p62 expression levels were significantly decreased at both the pre-onset and onset stages of ALS disease in Tg(SOD1*G93A)1Gur mice compared with control mice, but these proteins were markedly increased at the progression stage. LC3 protein expression did not change during progression of ALS. These findings suggest that PIK3R4 likely participates in the prevention of ALS progression. This study was approved by the Ethics Committee for Animal Care and Use of Jiangxi Provincial People’s Hospital, Affiliated People’s Hospital of Nanchang University (approval No. 2020025) on March 26, 2020.

Key words: amyotrophic lateral sclerosis, autophagy, LC3, p62, PC12 cell, phosphoinositide-3-kinase regulatory subunit 4, spinal cord, Tg(SOD1*G93A)1Gur mice