# Development of CHCHD2-linked PD mouse models

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2020 · $434,500

## Abstract

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.

## Key facts

- **NIH application ID:** 9877247
- **Project number:** 1R21NS114765-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Han-Xiang Deng
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $434,500
- **Award type:** 1
- **Project period:** 2019-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9877247

## Citation

> US National Institutes of Health, RePORTER application 9877247, Development of CHCHD2-linked PD mouse models (1R21NS114765-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9877247. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*