Eric Shoubridge, at McGill University in Montreal, Québec, was awarded an MDA research grant totaling $287,169 over three years to study a new mitochondrial gene linked to ALS (amyotrophic lateral sclerosis). Mitochondria are the tiny energy factories found inside most cells.

If successful, Shoubridge’s work could lead to important insights into the involvement of mitochondria in ALS and reveal new drug targets.

Please describe your current research.

Mitochondrial dysfunction lies at the heart of a growing number of neurodegenerative disorders, and although it has been suggested to contribute to some forms of ALS, the evidence to date has not been compelling. The recent discovery of mutations in a bona fide mitochondrial gene, CHCHD10, in patients with autosomal dominant ALS, frontotemporal dementia (FTD), myopathy and other motor neuron diseases, clearly implicates mitochondrial pathology as an important cause of disease in some patients.

The association of ALS and FTD with mutations in RNA-binding proteins like FUS and TDP-43 raises the intriguing possibility that CHCHD10 is part of a common disease-associated protein network. CHCHD10 belongs to a family of proteins containing a specific motif that targets it to mitochondria, but its function remains almost completely unknown.

The objective of this research is to elucidate the normal function of this protein and the mechanism of pathogenesis in ALS. Our strategy will be to work out the basic biology of CHCHD10 in human cell culture models (myoblasts, fibroblasts, HEK cells) and to carry out the crucial experiments in motor neurons from patient-derived induced pluripotent stem cells. We will investigate the composition of CHCHD10 protein complexes and determine interacting partners by biochemical and molecular biology techniques and comprehensively evaluate mitochondrial function in response to loss and gain of function. Finally, we will make a model of the disease-causing mutations in zebrafish where we will directly be able to evaluate the requirement of CHCHD10 for normal motor neuron function in vivo.

What is the expected outcome of this research?

We hope to uncover the normal function of CHCHD10 in mitochondrial function and to show how mutations in the gene interfere with this function and ultimately compromise the viability of motor neurons. We also hope to find out whether mitochondrial dysfunction plays a broader role in other causes of familial ALS, perhaps mediated through CHCHD10.

How will your research lead to treatments and cures?

Our research will not lead directly to a cure, but we hope that the zebrafish will prove to be a good model for the disease and will thus serve as a potential screening tool for compounds that might delay or halt disease progression.

Why is it important that MDA continue to fund research in ALS?

ALS is a devastating disease for which there is no known cure. Investigating the rarer causes of inherited forms of the disease may give us a broader understanding of the range of mechanisms that compromise motor neuron function.

What do you feel people impacted by ALS can have the most hope about with respect to research right now?

At present we have an unprecedented range of genetic and biochemical tools that allow us to deeply investigate mechanisms of pathogenesis. There has never been a more exciting time to be involved in basic research directed towards understanding the mechanisms of disease.

Does your work have any potential implications for other disease fields?

Our work may have implications for other neurodegenerative conditions like Parkinson’s Disease (PD) as we have already found that CHCHD10 forms a tight complex with a closely related gene, CHCHD2, which has recently been discovered to be a risk factor for PD.

To learn more about how you can #EndALSwithMDA, visit mda.org.