Title : CHCHD2 p.Thr61Ile knock-in mice exhibit motor defects and neuropathological features of Parkinson’s disease
Abstract:
Parkinson's Disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Although the etiology of PD remains elusive, mounting evidence suggests a complex interplay of genetic and environmental factors. The p.Thr61Ile (p.T61I) mutation in the coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) gene was identified as a causative factor in PD. However, the pathogenic mechanisms of the CHCHD2 mutation in PD remain incompletely unclear. Few existing mouse models of CHCHD2-related PD completely replicate the features of PD, and there have been no reports of transgenic or knock-in (KI) mouse models with CHCHD2 mutations. Here, we present a novel CHCHD2 p.T61I KI mouse model that recapitulates key pathological and behavioral features of PD. We also generated DA neurons from induced pluripotent stem cells (iPSCs) carrying the CHCHD2 p.T61I mutation to elucidate the underlying disease mechanisms. Our novel mouse model exhibited progressive motor impairments reminiscent of PD symptoms, including accelerated mortality and progressive motor deficits. Histological analyses revealed a significant reduction in DA neuron density in the SNpc accompanied by the accumulation of α-synuclein aggregates in the brains, recapitulating key neuropathological hallmarks of PD observed in human patients. The mitochondria in KI mouse brains and iPSC-derived DA neurons carrying the CHCHD2 p.T61I mutation exhibited abnormal morphology and impaired function. Mechanistically, proteomic and RNA sequencing analysis revealed that the 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, the findings from our study validate the utility of this novel mouse model for investigating PD pathogenesis and provide insights into the role of IDE in dopaminergic neuron degeneration. This model holds promise for the development of novel therapeutic strategies targeting PD-specific pathological mechanisms.
Audience Take Away Notes:
- Researchers can utilize the insights gained from this study to better understand the genetic basis of PD and the underlying molecular mechanisms contributing to the disease. Researchers can use the newly developed animal model as a tool for investigating the effects of specific genetic mutations on PD pathogenesis, testing potential therapeutic interventions, and identifying biomarkers for early diagnosis and prognosis.
- Clinicians can gain insights into PD progression and underlying mechanisms, aiding in the development of targeted diagnostic and therapeutic approaches for better patient management.
- Faculty members in genetics, neuroscience, neurology, and related disciplines can use this research to expand their knowledge base, incorporate new findings into their research, and potentially inspire further research directions in the field.
- The new insights gained from this research could contribute to the development of more accurate diagnostic tools and targeted therapies, indirectly benefiting designers working in the medical devices or pharmaceuticals.
- Advancement of scientific knowledge in the field of neurodegenerative diseases.
- Potential for the development of personalized medicine approaches for PD patients.
- Contribution to the discovery of novel therapeutic targets for PD treatment.
