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 ROS. Successful completion of the proposed studies should have a significant impact on understanding the pathogenesis underlying CHCHD2-linked PD, especially for providing critical information to distinguish ?loss-of-function?, ?gain-of-function? and ?dominant-negative effect? mechanisms from each other. Moreover, because these mouse models cover all three types of genetic modifications, they will provide the PD research community with a complete series of much needed mouse models for more comprehensive studies of the molecular mechanism, which may provide important mechanistic insight for the rational design of therapeutic strategies. In addition, since the clinical features of CHCHD2-linked PD are compatible with those of sporadic PD, the outcome of this study may also have important implications in understanding the more complicated pathogenic mechanisms in sporadic PD as well.

Public Health Relevance

Mutations in CHCHD2 have been linked to autosomal dominant, late-onset Parkinson's disease. But the disease mechanism is largely unknown. In this application, we propose to develop and characterize a complete series of four CHCHD2-linked PD mouse models, which cover all three types of genetic modifications, including knockout, knockin and transgenic overexpression. Successful completion of the proposed studies should provide important information for understanding pathogenic mechanism underlying CHCHD2-linked PD. These mouse models will also provide the PD research community with new tools for further mechanistic studies and therapeutic testing.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Sieber, Beth-Anne
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Northwestern University at Chicago
Schools of Medicine
United States
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