2. Academic Validation
  3. CHCHD2 p.Thr61Ile knock-in mice exhibit motor defects and neuropathological features of Parkinson's disease

CHCHD2 p.Thr61Ile knock-in mice exhibit motor defects and neuropathological features of Parkinson's disease

  • Brain Pathol. 2022 Nov 2;e13124. doi: 10.1111/bpa.13124.
Liyuan Fan 1 2 3,  Shuo Zhang 1 2 3,  Xinwei Li 1 2 3,  Zhengwei Hu 1 2 3,  Jing Yang 1 3,  Shuyu Zhang 4,  Huimin Zheng 1 3,  Yun Su 1 3,  Haiyang Luo 1 3,  Xinjing Liu 1 3,  Yu Fan 1 2 3,  Huifang Sun 1 2 3,  Zhongxian Zhang 5,  Jinxin Miao 5 6,  Bo Song 1 3,  Zongping Xia 1 3 7,  Changhe Shi 1 3 8,  Chengyuan Mao 1 3 5,  Yuming Xu 1 3 8
Affiliations

Affiliations

  • 1 Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
  • 2 Academy of Medical Sciences of Zhengzhou University, Zhengzhou, China.
  • 3 Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
  • 4 Neuro-Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 5 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, China.
  • 6 Academy of Chinese Medicine Science, Henan University of Chinese Medicine, Zhengzhou, China.
  • 7 Clinical Systems Biology Laboratories, Zhengzhou University, Zhengzhou, China.
  • 8 Institute of Neuroscience, Zhengzhou University, Zhengzhou, China.
PMID: 36322611 DOI: 10.1111/bpa.13124
Abstract

The p.Thr61Ile (p.T61I) mutation in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) was deemed a causative factor in Parkinson's disease (PD). However, the pathomechanism of the CHCHD2 p.T61I mutation in PD remains unclear. Few existing mouse models of CHCHD2-related PD completely reproduce the features of PD, and no transgenic or knock-in (KI) mouse models of CHCHD2 mutations have been reported. In the present study, we generated a novel CHCHD2 p.T61I KI mouse model, which exhibited accelerated mortality, progressive motor deficits, and dopaminergic (DA) neurons loss with age, accompanied by the accumulation and aggregation of α-synuclein and p-α-synuclein in the brains of the mutant mice. The mitochondria of mouse brains and induced pluripotent stem cells (iPSCs)-derived DA neurons carrying the CHCHD2 p.T61I mutation exhibited aberrant morphology and impaired function. Mechanistically, proteomic and RNA sequencing analysis revealed that p.T61I mutation induced mitochondrial dysfunction in aged mice likely through repressed insulin-degrading Enzyme (IDE) expression, resulting in the degeneration of the nervous system. Overall, this CHCHD2 p.T61I KI mouse model recapitulated the crucial clinical and neuropathological aspects of patients with PD and provided a novel tool for understanding the pathogenic mechanism and therapeutic interventions of CHCHD2-related PD.

Keywords

CHCHD2; Parkinson's disease; insulin-degrading enzyme; mitochondria; mouse model.

Figures
Products