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Research team identifies human disease gene with the help of fruit flies

by CIFAR Apr 2 / 12

CIFAR Fellow Eric A. Shoubridge with his colleagues at McGill University collaborated with researchers at Baylor College of Medicine in Houston to discover a gene that causes neurodegeneration in fruit flies and a progressive neurodegenerative disease that leads to coordination problems in humans called Recessive Ataxia (ARSAL).

The gene produces a protein in the mitochondria – an organelle in the cell that produces the majority of a cell’s energy supply. Defects in genes like this are known to be associated with human metabolic and neurological diseases. By discovering that the gene caused neurodegeneration in fruit flies, the team was then able to use this knowledge to discover that ARSAL was caused by the same gene in humans. The group’s findings were published in PLoS Biology.

“This study underscores the increasingly recognized importance of mitochondrial dysfunction in neurological disorders,” explains Dr. Shoubridge. “It also illustrates the important role of model organisms in the discovery and characterization of neurological disease genes.”

In this study, researchers at Baylor College first found that fruit flies with degenerative neurons in their eyes also had defects in the gene Aats-met, which codes for a mitochondrial protein. The team’s finding was especially interesting because humans have their own version of the same gene, called MARS2. This sparked the question of whether defects in MARS2 also cause disease in humans.

With this in mind, the team at Baylor searched through previously published studies, to see if there were any human neurological disorders known to be caused by defects in the region of the genome where MARS2 is located. The team landed upon the published work from the group at McGill University, who discovered in 2006 that the human disease ARSAL was caused by defects in the region of DNA where MARS2 is found. However, the precise gene responsible for the disease was still a mystery.

The team at Baylor connected with the researchers at McGill, who were then able to use the new knowledge from the fruit fly and investigate the role of the human gene MARS2 in ARSAL. As Dr. Shoubridge explains, “the genetic defects in the ARSAL patients were particularly difficult to identify. The fact that research in the fruit fly identified MARS2 mutations encouraged my colleague Dr. Brais’ lab to persist in their analysis of this locus.” They discovered that ARSAL patients did have rearrangements of the MARS2 gene that impaired the function of mitochondria. Dr. Shoubridge’s lab played a role by investigating the effect of the gene rearrangements. His lab found that the rearrangements decreased the production of the MARS2 protein as well as other mitochondrial proteins. The patient cells also had similar abnormalities as fruit flies with mutations in their Aats-met gene.

This study demonstrates how colleagues working in distant labs can come together to collaborate and shed new light on important causes of human diseases. It also shows how we can strategically use fruit fly models to identify human disease genes, and potentially identify treatment approaches in patients.