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Single gene controls many signaling pathways

 

Dr. Kapatos and his research team were the first to identify DNA control elements and transcription factors that are required for GTP cyclohydrolase expression and regulation. Pictured from left (front row) are: Mika Shimofi, Greg Kapatos, Amy Meyer, (back row) Navid Seraji, Kei Hirayama and Christina Hayes.

 

Production of the signaling molecules dopamine, norepinephrine, epinephrine, serotonin, and nitric oxide within the brain is dependent upon a single enzyme and the gene that encodes it, according to Gregory Kapatos, PhD, professor of psychiatry and behavioral neurosciences. “If we can find out how this gene is regulated, then we can develop new tools to control the synthesis of these neurotransmitters,” he said, noting that this could have implications for the understanding and treatment of disorders such as hereditary progressive dystonia and Parkinson’s disease.

Specifically, Dr. Kapatos is studying the gene for the protein GTP cyclohydrolase, the rate-limiting enzyme in the pathway that makes a substance known as tetrahydrobiopterin. “Compounds like tetrahydrobiopterin serve as the pigments in the wings of butterflies,” he said. While not used as a pigment in man, tetrahydrobiopterin is the essential cofactor for the enzymes that synthesize these neurotransmitters.

“Tetrahydrobiopterin is a molecule that, until recently, most people never paid much attention to because they believed the cofactor was present in tremendous excess, meaning that neurons could make as much or as little of it as they liked and it wouldn’t make any difference with respect to neurotransmitter levels. We and others have since shown that this is not the case and that the cofactor is actually present at very low amounts.” Dr. Kapatos believes if his research group can learn how to turn the gene for GTP cyclohydrolase on and off, then they can regulate the production of tetrahydrobiopterin and, subsequently, the synthesis of these important signaling molecules.

With a three-year $787,500 grant renewal from the National Institute of Neurological Diseases and Stroke, Dr. Kapatos and co-investigator Kei Hirayama, PhD, assistant professor, are beginning their 12th year of studying the regulation of this gene. “I have been studying this biochemical pathway since I was a staff fellow at the National Institutes of Health because mutations that effect tetrahydrobiopterin metabolism result in a number of childhood disorders,” he explained. “The GTP cyclohydrolase gene is also very interesting because when both alleles carry mutations, all children have mental retardation and severe movement disorders, but if only a single allele is mutated and you happen to be female, you will have normal intelligence and only a mild movement disorder known as hereditary progressive dystonia. Brothers of these affected young girls, on the other hand, can carry the identical genetic defect but do not develop the disease,” he said. The mechanism for this sex dependence remains just one of the mysteries surrounding the disorder because the gene for GTP cyclohydrolase is not located on either of the sex chromosomes. “We have shown, however, that GTP cyclohydrolase is expressed at lower levels in the brains of female mice than males, which will allow us to study these sex differences,” he added.

Hereditary progressive dystonia is also unusual in that many affected individuals don’t carry mutations within the coding region of the gene, yet they have low GTP cyclohydrolase activity. “This has led us to clone and study the rat and human GTP cyclohydrolase gene promoters,” he said, adding that his lab was the first to identify DNA control elements and transcription factors that are required for GTP cyclohydrolase expression and regulation. “We have found that minor mutations within the promoter sequence, mutations that would not show up in current genetic screens for hereditary progressive dystonia, can dramatically decrease GTP cyclohydrolase gene expression,” he added.

Whether similar mutations within the GTP cyclohydrolase gene promoter are a cause of hereditary progressive dystonia awaits further study.

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