Skip to content
Project Directory
  • Français
Donate Now
  • Français
  • About
    • What We Do
    • EDI Action Plan
    • Leadership
    • Team
    • Annual Report
    • Publications
    • Careers
  • Brain Conditions
    • One Brain
    • ALS
    • Autism (ASD)
    • Brain Cancer
    • Brain Injury
    • Dementia
    • Epilepsy
    • Mental Illness
    • Multiple Sclerosis
    • Parkinson’s
    • Stroke
    • More
  • Research
    • Programs
    • Funding Opportunities
    • Program Partners
    • Announcements
  • Impact
    • Research Impact Stories
    • Equity, Diversity and Inclusion
    • Brain Health in Indigenous Communities
    • Women’s Brain Health
    • Mind Over Matter
  • How You Can Help
    • Ways to Give
    • Start a Fundraiser
    • Workplace Giving
    • The Great Minds

Funded Grants

Back to results

Investigating the role of mutations in CHCHD10 using ALS cell and zebrafish genetic models

Project Overview

CHCHD10 is a nuclear encoded mitochondrial protein of the twin Cx9C family whose cellular function remains to be fully understood. Several dominantly inherited missense mutations have been reported in patients with amyotrophic lateral sclerosis (ALS), some of which appear to be gain of function while others are haploinsufficient. In the mitochondrial intermembrane space, CHCHD10 forms a complex of unknown function with its paralogue CHCHD2, a protein that has been linked to rare cases of Parkinson disease. Using a combination of patient cell lines and novel zebrafish CRISPR models we propose to study the function of CHCHD10 and CHCHD2 and the cellular and molecular basis for pathology. Preliminary data on human fibroblasts from an ALS/FTD patient and from CRISPR/Cas9 knockouts have demonstrated that both proteins are required for aerobic metabolism, and that loss of function variants result in assembly defects in one or more of the oxidative phosphorylation (OXPHOS) complexes. Patient cells (CHCHD10R15L) challenged with an nutrient stress exhibit a severe growth defect and upregulate both a mitochondrial and endoplasmic reticulum (ER) unfolded protein response, the latter mediated through the IRE1/XBP1 pathway. We hypothesize that this might be a general response to gain or loss of function CHCHD10 variants, and we propose to test this, and to try to identify how mitochondrial stress is signaled to the cytoplasm/ER in this model. We will also use CRISPR/Cas9 editing to disrupt components of the UPR responses to test the effects in cell survival, apoptosis, and autophagy. The results of these studies will be used to inform experiments using in vivo models in zebrafish, including the characterization of motor defects, neuromuscular junction (NMJ) denervation, as well as mitochondrial dysfunction. To this end a Chchd10 and Chchd2 knockout, as well as a Chchd10P83L knockin model (analogous to the human CHCHD10P80L variant) have been created. Preliminary results suggest that loss of Chchd10, or Chchd2 or expression of the Chchd10P83L variant leads to reduced survival, weight as well as aberrant muscle histology in adult fish. We hypothesize that our cell and zebrafish models offers a unique opportunity to explore the mechanisms that culminate in neurodegeneration in patients with mutations in CHCHD10 and may likely add to the complex, and as of yet to be fully understood role, that abnormal mitochondrial play in ALS.

Principal Investigator

Gary Armstrong , Montreal Neurological Institute, McGill University

Team Members

Eric Shoubridge, Montreal Neurological Institute, McGill University

Partners and Donors

ALS Canada

Project Complete

Investigating the role of mutations in CHCHD10 using ALS cell and zebrafish genetic models

  • Grant Type

    Team grants

  • Area of research

    Neurodegeneration

  • Disease Area

    ALS

  • Competition

    ALS Canada - Brain Canada Discovery Grants

  • Province

    Québec

  • Start Date

    2021

  • Total Grant Amount

    $125,000

  • Health Canada Contribution

    $62,500

Contact Us

1200 McGill College Avenue
Suite 1600, Montreal, Quebec
H3B 4G7

+1 (514) 989-2989 info@braincanada.ca

Please note all online donations will receive an electronic tax receipt, issued by Brain Canada Foundation.

Our Donors

Playing with Marbles Podcast

Join us and take a journey to the real last great frontier – the brain.

Listen

Subscribe to Brain News

Receive our monthly electronic newsletter with updates on funded projects, upcoming events and breakthroughs in brain research.

Sign Up

Territorial acknowledgement

The offices of Brain Canada Foundation are located on the traditional, ancestral territory of the Kanien'kehá:ka Peoples, a place which has long served as a site of meeting and exchange amongst nations. We honour and pay respect to elders past, present and emerging, and dedicate ourselves to moving forward in the spirit of partnership, collaboration, and reconciliation. In our work, we focus our efforts on the Truth and Reconciliation Commission’s Calls to Action, particularly those that pertain to improving health for Indigenous Peoples and that focus on advancing our own learning on Indigenous issues.

© 2025 Brain Canada Foundation

Registration number: 89105 2094 RR0001

  • Terms and Conditions
  • Privacy Policy

Design by Field Trip & Co

  • About
    • What We Do
    • EDI Action Plan
    • Leadership
    • Team
    • Annual Report
    • Publications
    • Careers
  • Brain Conditions
    • One Brain
    • ALS
    • Autism (ASD)
    • Brain Cancer
    • Brain Injury
    • Dementia
    • Epilepsy
    • Mental Illness
    • Multiple Sclerosis
    • Parkinson’s
    • Stroke
    • More
  • Research
    • Programs
    • Funding Opportunities
    • Program Partners
    • Announcements
  • Impact
    • Research Impact Stories
    • Equity, Diversity and Inclusion
    • Brain Health in Indigenous Communities
    • Women’s Brain Health
    • Mind Over Matter
  • How You Can Help
    • Ways to Give
    • Start a Fundraiser
    • Workplace Giving
    • The Great Minds
Project Directory
Donate Now