Development of CHCHD2-linked PD mouse models

Mutations in CHCHD2 have been linked to an autosomal dominant type of PD. Although the pathology of CHCHD2-linked PD is not known, the clinical features are compatible with those in sporadic PD, including mostly late-onset and good response to levodopa treatment. CHCHD2 encodes a coiled-coil-helix-coiled-coil-helix domain (CHCHD)-containing protein, which primarily localizes to the intermembrane space of mitochondria. The pathogenic mechanism of CHCHD2-linked PD remains largely unknown. Early studies of CHCHD2 in Drosophila models suggest a “loss-of-function” mechanism, as shown by the observations that Drosophila models either deficient of CHCHD2 or expressing PD-associated mutants displayed structural and functional abnormalities of mitochondria, leading to dopaminergic neurodegeneration and motor dysfunction. However, whether these findings in invertebrate flies could be directly applied to mammals remains to be determined. To date, studies of CHCHD2 function and the pathogenic mechanism of CHCHD2-linked PD in mammals have not been carried out, due to the lack of relevant mammalian models. CHCHD2 appears to be the first mitochondrial intermembrane space protein that is convincingly involved in autosomal dominant and late-onset PD, relevant mouse models are much needed resources to address the physiological function of CHCHD2 and pathogenic mechanism, by which mutant CHCHD2 causes PD. In this application, we propose in specific aim 1 to develop a complete series of three presentative types of CHCHD2 mouse models, including knockout, knockin and transgenic overexpression (both CHCHD2-Wt and CHCHD2-T61I). In specific aim 2. We propose to characterize the motor phenotype and brain pathology of these four mouse models. Since CHCHD2 is a protein known to be present in the mitochondrial intermembrane space, and mutant CHCHD2 is likely to affect mitochondrial generation of ATP and ROS. Therefore, we will also examine mitochondrial ATP levels as well as mitochondrial