Neural Regeneration Research ›› 2024, Vol. 19 ›› Issue (8): 1828-1834.doi: 10.4103/1673-5374.389356

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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).

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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