2. Academic Validation
  3. CHIP protects against MPP+/MPTP-induced damage by regulating Drp1 in two models of Parkinson's disease

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

  • Aging (Albany NY). 2021 Jan 2;13(1):1458-1472. doi: 10.18632/aging.202389.
Zhengwei Hu 1 2,  Chengyuan Mao 1,  Hui Wang 1,  Zhongxian Zhang 3,  Shuo Zhang 1 2,  Haiyang Luo 1 2,  Mibo Tang 1 2,  Jing Yang 1,  Yanpeng Yuan 1,  Yanlin Wang 1,  Yutao Liu 1,  Liyuan Fan 1 2,  Qimeng Zhang 1,  Dabao Yao 1,  Fen Liu 1 2,  Jonathan C Schisler 4 5,  Changhe Shi 1 6 7,  Yuming Xu 1 6 7
Affiliations

Affiliations

  • 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.
PMID: 33472166 DOI: 10.18632/aging.202389
Abstract

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.

Keywords

CHIP; Drp1; MPTP; Parkinson’s disease; gene knockin.

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