Oklahoma Medical Research Foundation scientists — and a lot of tiny fish — were instrumental in a worldwide effort to pinpoint the cause of a rare, severe neurodevelopmental disorder that shares some characteristics with Parkinson’s disease. Their work could lead to greater insights into Parkinson’s.
Following seven years of research, an international team determined that a specific genetic mutation was responsible for causing the disorder in 45 people, representing 28 families on several continents, including 11 people from six families in the U.S.
The unnamed disease begins early in life and progresses to significant motor and cognitive deterioration as the person reaches adulthood.
OMRF scientist Gaurav Varshney, Ph.D., and his team led by postdoctoral researcher Sheng-Jia Lin, Ph.D., helped determine the cause by matching patient symptoms with those of a paperclip-sized zebrafish model sharing the same genetic variant. They created the model at OMRF using gene-editing technology called CRISPR.
Varshney’s lab studies human disease through zebrafish. More than 80% of human genes associated with disease have a counterpart gene in the species.
Varshney’s collaborator in London, Reza Maroofian, Ph.D., identified three members from the same family who shared a mutation on the gene ACBD6 and exhibited similar neurological symptoms. In 2020, as the search grew to identify other cases, the research team asked Varshney to test the effects of that mutation in a zebrafish model.
The ACBD6 gene is crucial in certain cellular and protein-modification processes. Research has shown that disruptions of these processes can cause degenerative brain diseases.
Varshney and Lin’s zebrafish model confirmed suspicions about the cause of the human condition. During three years of study, the team found the affected zebrafish exhibited the same clinical symptoms as their human counterparts.
The team’s findings were published in the journal Brain.
“Zebrafish are the perfect model to study genetic diseases because the larvae are transparent and grow externally,” OMRF’s Lin said. “This allows us to easily monitor their brain development and behavior.”
Next, the international team will try to identify a way to block that genetic variant to prevent or treat the condition. Further studies may shed light on genetic causes and pathways leading to this and other neurodevelopmental diseases.
“With the knowledge gained by generating this zebrafish model, we hope to better understand how this genetic mutation relates to disease progression,” Varshney said. “While this research involved a rare disorder, we may discover that our findings have applicability to the much more common and related disease of Parkinson’s.”