Researchers at Baylor College of Medicine and the Jan and Dan Duncan Neurological Institute at Texas Children's Hospital have identified new genes that regulate dopamine levels in the brain, using fruit flies as a model. The study, published in iScience, aimed to improve understanding of how dopamine is controlled in the body, which could help address diseases where dopamine function is disrupted.
Dopamine is important for movement, learning, motivation, and sleep. Problems with dopamine are linked to conditions such as Parkinson's disease, depression, and sleep disorders. While much is known about how dopamine works in the brain, less is understood about how its levels are regulated.
The research team used RNA interference (RNAi) to silence specific genes in fruit flies and observed changes in pigmentation. They then checked if these genes also affected dopamine levels and behaviors like sleep.
"We began by working with more than 450 genes that have been proposed to affect flies' body color. Using our gene-silencing technique, we confirmed 153 that consistently changed pigmentation," said Yamamoto. "Interestingly, 85% of these genes are conserved in humans, and more than half are linked to neurological disorders such as autism, epilepsy and intellectual disability."
The researchers found that out of the 153 pigmentation-related genes identified, 50 were associated with unusual movement or sleep patterns when silenced in dopamine-producing neurons. This suggests a possible role for these genes in brain function.
They focused on 35 genes present both in flies and humans that had strong effects on pigmentation and behavior. Of these, eleven significantly altered dopamine levels—mostly reducing them—but there was no clear connection between external color changes and internal dopamine levels.
"We then narrowed our study to two genes, mask and clu. Both genes reduced brain dopamine when silenced," Yamamoto said. "Further experiments revealed that mask lowers dopamine by reducing the expression of tyrosine hydroxylase, the key enzyme for dopamine synthesis. The clu gene also reduced dopamine, but through a different mechanism."
Silencing mask led to changes in fly sleep patterns: they lost their usual anticipation of light before dawn and slept more during this period. Feeding L-DOPA reversed this effect; silencing mask also made caffeine less effective at promoting wakefulness—a process dependent on dopamine.
In contrast, silencing clu increased sleep but did not affect light anticipation or respond to L-DOPA treatment. This suggests clu affects dopamine indirectly.
By focusing on cuticle pigmentation-related genes in fruit flies, researchers identified mask and clu as regulators of brain dopamine levels. These findings may lead to new approaches for restoring normal dopamine function related to neurological disorders such as addiction or schizophrenia.
Other contributors included Samantha L. Deal, Danqing Bei, Shelley B. Gibson, Harim Delgado-Seo, Yoko Fujita, Kyla Wilwayco, Elaine S. Seto and Amita Sehgal from Baylor College of Medicine; Duncan NRI; and University of Pennsylvania.
Funding came from startup funds at Duncan NRI; Department of Molecular and Human Genetics at Baylor College of Medicine; IRACDA program at University of Pennsylvania (K12GM081259); Howard Hughes Medical Institute; Intellectual and Developmental Disabilities Research Center (U54HD083092); Eunice Kennedy Shriver National Institute of Child Health and Human Development.
