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

Zhengwei Hu,Fen Liu,Yutao Liu,Mibo Tang,Liyuan Fan,Jonathan C Schisler,Changhe Shi,Qimeng Zhang,Haiyang Luo,Chengyuan Mao,Zhongxian Zhang,Hui Wang,Yanpeng Yuan,Dabao Yao,Shuo Zhang,Yanlin Wang,Jing Yang,Yuming Xu

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.

Highlights

Parkinson’s disease (PD), which is characterized by clinical features such as bradykinesia, tremor, rigidity, and autonomic dysfunction, is the second most common neurodegenerative disease [1]
We studied the effect of Carboxyl terminus of Hsp70-interacting protein (CHIP) overexpression in vivo on the amelioration of motor impairments, cell viability, and mitochondrial homeostasis in MPTP-induced PD models
This study explored the protective role of CHIP in cell and animal PD models

Summary

Introduction

Parkinson’s disease (PD), which is characterized by clinical features such as bradykinesia, tremor, rigidity, and autonomic dysfunction, is the second most common neurodegenerative disease [1]. Mitochondrial dysfunction is considered the core factor in the pathogenesis of PD. Mitochondria are highly dynamic organelles essential for energy conversion, and the high energy demand of neurons renders them vulnerable to mitochondrial dysfunction [3]. Disruption of mitochondrial dynamics has been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, Charcot-Marie-Tooth disease, and Huntington's disease [4,5,6]. Accumulating evidence from in vivo and in vitro PD models shows that modulation of mitochondrial dynamics can attenuate PD-associated impairments. A potential avenue of PD treatment involves preserving the normal function of mitochondria [8]

Methods

Results

Conclusion