中国神经再生研究(英文版) ›› 2024, Vol. 19 ›› Issue (8): 1828-1834.doi: 10.4103/1673-5374.389356

• 原著:退行性病与再生 • 上一篇    下一篇

内质网应激节抗增殖蛋白2介导线粒体自噬参与帕金森病发展的新机制

  

  • 出版日期:2024-08-15 发布日期:2024-01-03
  • 基金资助:
    河南省重点科技攻关项目(222102310351);洛阳市2022年医疗卫生引导科技计划项目(2022057Y);河南省医学科学技术研究计划省部级协办项目(SBGJ202002099)

A novel mechanism of PHB2-mediated mitophagy participating in the development of Parkinson’s disease

Yongjiang Zhang1, #, Shiyi Yin1, #, Run Song1, Xiaoyi Lai1, Mengmeng Shen1, Jiannan Wu1, *, Junqiang Yan1, 2, *   

  1. 1Key Laboratory of Neuromolecular Biology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan Province, China; 2Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan Province, China
  • Online:2024-08-15 Published:2024-01-03
  • Contact: Jiannan Wu, MS, wujiannan_haust@126.com; Junqiang Yan, MD, PhD, yanjq@haust.edu.cn.
  • Supported by:
    This work was supported by the Key Science and Technology Research of Henan Province, No. 222102310351 (to JW); Luoyang 2022 Medical and Health Guiding Science and Technology Plan Project, No. 2022057Y (to JY); Henan Medical Science and Technology Research Program Province-Ministry Co-sponsorship, No. SBGJ202002099 (to JY).

摘要:

内质网应激和线粒体功能障碍在帕金森病中起着重要的作用,但其调节机制尚不明确。抗增殖蛋白2是一种新发现的线粒体内膜自噬受体,其在帕金森病中的作用尚不明朗。PERK是内质网应激下细胞命运的调节因子,Parkin是未折叠蛋白反应的靶点,受到PERK的调节。目前尚不清楚PERK是否可通过Parkin调节抗增殖蛋白2介导的线粒体自噬。此次实验以1-甲基-4-苯基-1,2,3,6-四氢吡啶诱导建立帕金森病小鼠模型,使用腺相关病毒敲低抗增殖蛋白2表达,结果可见模型小鼠多巴胺能神经元缺失以及运动障碍明显加重,而过表达抗增殖蛋白2则可减轻这些症状。进一步以1-甲基-4-苯基吡啶诱导SH-SY5Y细胞模拟帕金森病,发现过表达Parkin可增加抗增殖蛋白2和微管相关蛋白1轻链3的共定位,并促进线粒体自噬。此外,1-甲基-4-苯基吡啶还可通过磷酸化PERK调节Parkin参与抗增殖蛋白2介导的线粒体自噬。实验结果提示,抗增殖蛋白2可与内质网应激和Parkin的相互作用参与帕金森病的发展。

https://orcid.org/0000-0002-2728-0546 (Yongjiang Zhang); https://orcid.org/0000-0002-5116-7973 (Shiyi Yin); https://orcid.org/0000-0001-9535-7296 (Run Song); https://orcid.org/0000-0003-0058-0802 (Xiaoyi Lai); https://orcid.org/0000-0001-6018-4612 (Jiannan Wu); https://orcid.org/0000-0002-6489-2824 (Junqiang Yan)

关键词: 帕金森病, 线粒体自噬, 氧化应激, 多巴胺能神经元, 活性氧, 抗增殖蛋白2, Parkin, PERK, 微管相关蛋白1轻链3

Abstract: Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson’s disease, but the regulatory mechanism remains elusive. Prohibitin-2 (PHB2) is a newly discovered autophagy receptor in the mitochondrial inner membrane, and its role in Parkinson’s disease remains unclear. Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is a factor that regulates cell fate during endoplasmic reticulum stress. Parkin is regulated by PERK and is a target of the unfolded protein response. It is unclear whether PERK regulates PHB2-mediated mitophagy through Parkin. In this study, we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson’s disease. We used adeno-associated virus to knockdown PHB2 expression. Our results showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson’s disease. Overexpression of PHB2 inhibited these abnormalities. We also established a 1-methyl-4-phenylpyridine (MPP+)-induced SH-SY5Y cell model of Parkinson’s disease. We found that overexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3, and promoted mitophagy. In addition, MPP+ regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of PERK. These findings suggest that PHB2 participates in the development of Parkinson’s disease by interacting with endoplasmic reticulum stress and Parkin.

Key words: endoplasmic reticulum, dopaminergic neuron, microtubule-associated protein 1 light chain 3, mitophagy, oxidative stress, Parkin, Parkinson’s disease, PKR-like endoplasmic reticulum kinase, reactive oxygen species, prohibitin-2