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Assessment of Sensorimotor Function in Mouse Models of Parkinson's Disease
Published on: June 17, 2013
CHCHD2 p.Thr61Ile knock-in mice exhibit motor defects and neuropathological features of Parkinson's disease
Liyuan Fan1,2,3, Shuo Zhang1,2,3, Xinwei Li1,2,3
1Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
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.
Insights
A novel mouse model reveals that the CHCHD2 p.T61I mutation causes Parkinson's disease (PD) features, including motor deficits and neuron loss. This model offers insights into PD mechanisms and potential treatments.
Area of Science:
- Neuroscience
- Genetics
- Mitochondrial Biology
Background:
- The p.Thr61Ile (p.T61I) mutation in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) is linked to Parkinson's disease (PD).
- The exact pathomechanism of the CHCHD2 p.T61I mutation in PD is not fully understood.
- Existing mouse models do not completely replicate PD features, and CHCHD2 mutation-specific models are lacking.
Purpose of the Study:
- To generate and characterize a novel CHCHD2 p.T61I knock-in (KI) mouse model.
- To investigate the pathomechanism of the CHCHD2 p.T61I mutation in PD.
- To provide a tool for studying PD pathogenesis and therapeutic interventions.
Main Methods:
- Generation of a CHCHD2 p.T61I KI mouse model.
- Assessment of motor function, mortality, and dopaminergic neuron loss.
- Analysis of α-synuclein aggregation.
- Evaluation of mitochondrial morphology and function in brain and iPSC-derived dopaminergic neurons.
- Proteomic and RNA sequencing analysis.
Main Results:
- The CHCHD2 p.T61I KI mice exhibited accelerated mortality, progressive motor deficits, and age-dependent dopaminergic neuron loss.
- Accumulation and aggregation of α-synuclein and p-α-synuclein were observed in the brains of mutant mice.
- Mitochondria in mutant mouse brains and iPSC-derived dopaminergic neurons showed aberrant morphology and impaired function.
- Proteomic and RNA sequencing revealed that the p.T61I mutation repressed insulin-degrading enzyme (IDE) expression, leading to mitochondrial dysfunction and neurodegeneration.
Conclusions:
- The CHCHD2 p.T61I KI mouse model successfully recapitulates key clinical and neuropathological features of PD.
- The p.T61I mutation induces mitochondrial dysfunction, potentially via repressed IDE expression, contributing to neurodegeneration in PD.
- This novel KI mouse model serves as a valuable tool for understanding CHCHD2-related PD mechanisms and developing therapies.
