Research Paper Volume 13, Issue 1 pp 1458—1472

CHIP protects against MPP+/MPTP-induced damage by regulating Drp1 in two models of Parkinson’s disease

Zhengwei Hu1,2, *, , Chengyuan Mao1, *, , Hui Wang1, *, , Zhongxian Zhang3, , Shuo Zhang1,2, , Haiyang Luo1,2, , Mibo Tang1,2, , Jing Yang1, , Yanpeng Yuan1, , Yanlin Wang1, , Yutao Liu1, , Liyuan Fan1,2, , Qimeng Zhang1, , Dabao Yao1, , Fen Liu1,2, , Jonathan C. Schisler4,5, , Changhe Shi1,6,7, , Yuming Xu1,6,7, ,

  • 1 Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
  • 2 The Academy of Medical Sciences of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
  • 3 Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
  • 4 McAllister Heart Institute at The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
  • 5 Department of Pharmacology, and Department of Pathology and Lab Medicine at The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
  • 6 Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
  • 7 Institute of Neuroscience, Zhengzhou University, Zhengzhou, Henan, China
* Equal contribution

Received: November 19, 2019       Accepted: September 18, 2020       Published: January 2, 2021
How to Cite

Copyright: © 2021 Hu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson’s disease (PD). Carboxyl terminus of Hsp70-interacting protein (CHIP) is a key regulator of mitochondrial dynamics, and mutations in CHIP or deficits in its expression have been associated with various neurological diseases. This study explores the protective role of CHIP in cells and murine PD models. In SH-SY5Y cell line, overexpression of CHIP improved the cell viability and increased the ATP levels upon treatment with 1-methyl-4-phenylpyridinium (MPP+). To achieve CHIP overexpression in animal models, we intravenously injected mice with AAV/BBB, a new serotype of adeno-associated virus that features an enhanced capacity to cross the blood-brain barrier. We also generated gene knock-in mice that overexpressed CHIP in neural tissue. Our results demonstrated that CHIP overexpression in mice suppressed 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced damage, including movement impairments, motor coordination, and spontaneous locomotor activity, as well as loss of dopaminergic neurons. In vitro and in vivo experiments showed that overexpression of CHIP inhibited the pathological increase in Drp1 observed in the PD models, suggesting that CHIP regulates Drp1 degradation to attenuate MPP+/MPTP-induced injury. We conclude that CHIP plays a protective role in MPP+/MPTP-induced PD models. Our experiments further revealed that CHIP maintains the integrity of mitochondria.


AAV: Adeno-associated virus; ATP: Adenosine triphosphatase; BBB: Blood-brain barrier; CCK8: Cell Counting Kit-8; CHIP: Carboxyl-terminus of Hsp70-interacting Protein; DAB: Diaminobenzidine; Drp1: Dynamin-related protein 1; Fis1: Fission 1; GAPDH: Glyceraldehyde-3-phosphate dehydrogenase; HRP: Horseradish peroxidase-conjugated; LDH: Lactate dehydrogenase; Mfn1: Mitofusin 1; Mfn2: Mitofusin 2; MPP+: 1-methyl-4-phenylpyridinium; MPTP: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MTR: MitoTracker Red; OGD: Oxygen-glucose deprivation; Opa1: Optic atrophy 1; PD: Parkinson’s disease; PINK1: PTEN-induced putative kinase 1; SNpc: Substantia nigra pars compacta; TH: Tyrosine hydroxylase.