# Pathological signatures of CHCHD10 dysfunction in ADRDs

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $402,500

## Abstract

Project Summary
The CHCHD10 gene coding for a mitochondrial protein is mutated in familial and sporadic
Frontotemporal Dementia (FTD), Amyotrophic Lateral Sclerosis (ALS), and mixed FTD-ALS. The
estimated prevalence of CHCHD10 mutations is 7.7% among FTD in the Chinese population and
0.68-2.6% among FTD-ALS patients of European descent, making CHCHD10 the second most
frequently mutated gene in FTD and FTD-ALS. We know that the FTD-ALS CHCHD10S59L
mutation and the ALS CHCHD10R15L mutation promotes CHCHD10 aggregation and
mitochondrial dysfunction. However, as only 1 patient with CHCHD10 mutation (ALS-linked
CHCHD10R15L) and no FTD patient with CHCHD10 mutation has come to autopsy, we do not
know the pathological signatures of CHCHD10-driven pathogenesis and to what extent such
signatures are present in sporadic diseases (i.e. FTD, FTD-ALS, AD). As misfolded proteins tend
to clog and inhibit the proteasome, such misfolded and aggregation-prone proteins are frequently
translocated into mitochondria as an alternative pathway for proteostasis. We recently generated
transgenic (Tg) mice expressing wild type (WT) CHCHD10WT, CHCHD10R15L, or CHCHD10S59L
driven by the neuronal mouse PrP promoter, which show clear pathophysiological phenotypes.
By taking advantage of mouse models and human postmortem tissues together with molecular,
biochemical, histochemical, proteomics, electrophysiological, and behavioral toolsets, this
proposal will test the overarching hypothesis that the loss of endogenous CHCHD10 (as seen in
sporadic ADRDs) and FTLD/ALS-linked CHCHD10 mutations drive diverse pathological
signatures resulting from disruptions in mitochondrial proteostasis and autophagic clearance of
proteotoxically challenged mitochondria, and that restoration of WT CHCHD10 represents a
viable strategy to mitigate proteotoxic burden and disease outcomes. Aim 1 will define the role of
wild type CHCHD10 in mitigating pathological phenotypes in vivo. Aim 2 will identify and validate
the neuropathological signatures of FTLD/ALS-linked CHCHD10 mutations. Aim 3 will determine
the role of mutant CHCHD10 in mitophagy flux in vivo.

## Key facts

- **NIH application ID:** 10235313
- **Project number:** 1R01NS122350-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** David E Kang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $402,500
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10235313

## Citation

> US National Institutes of Health, RePORTER application 10235313, Pathological signatures of CHCHD10 dysfunction in ADRDs (1R01NS122350-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10235313. Licensed CC0.

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