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

alexandrossfakianakis shared this article with you from Inoreader CHCHD2 p.Thr61Ile knock‐in mice exhibit motor defects and neuropathological features of Parkinson's disease via Brain Pathology We set out to study the biological role of the CHCHD2 p.T61I mutation in Parkinson's disease in vivo by generating a knock-in mouse model harbouring the mutation. The mutant mice had accelerated mortality, progressive motor deficits, and the loss of dopaminergic neurons. α-synuclein and p-α-synuclein aggregations were observed in the brains of the mutant mice; these mice also exhibited an aberrant mitochondrial morphology and impaired mitochondrial function. Induced pluripotent stem cell-derived dopaminergic neurons carrying the CHCHD2 p.T61I mutation reproduced the impaired mitochondria. Proteomic and RNA sequencing analysis revealed that p.T61I mutation induced mitochondrial dysfunction in aged mice likely through repressed IDE expression, resulting in the degeneration of the nervous system. 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 mutatio n 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. View on Web

Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.