Genetic Mechanisms linked to Parkinson's Disease Uncovered (7/27/2008)

Researchers show direct pathway which could be targeted for drug therapy

A new genetic finding from a group of researchers at Brigham and Women's Hospital (BWH), the University of Wisconsin School of Medicine and Public Health (SMPH), and the University of Ottawa, may help pave the way for the discovery of therapies that could effectively treat Parkinson's disease (PD). Clemens Scherzer, MD, a neurologist and researcher at BWH, along with collaborators, showed that the build up of a certain protein is responsible for controlling the production of the gene, alpha-synuclein, which is a cause of PD. These findings appear online in the Proceedings of the National Academy of Science during the week of July 21, 2008 and will appear in a later print edition of the journal.

"This discovery is exciting because it allows for a paradigm shift in how researchers can search for a cure for Parkinson's disease. So far research has focused on ways to get rid of excess alpha-synuclein that is built up in the brain of patients with Parkinson's. Now, we can look for ways to lower the production of alpha-synuclein upfront," Scherzer said.

Patients with PD have clumps of alpha-synuclein in their brains and high levels of this protein kill off dopamine neurons and cause tremors and other symptoms of PD. While looking at blood tests for Parkinson's disease, the researchers noticed high levels of alpha-synuclein in the blood. Because alpha-synuclein was thought previously to be a gene found in the brain, its presence in the blood was surprising. Seeking to uncover the reason for the presence of this gene in blood, they used gene chips to look at whether or not any of the thousands of other genes active in blood was linked to alpha-synuclein. They discovered that there are actually three genes, called heme genes, which are responsible for carrying oxygen and transporting electrons through the blood, whose activity was in lock step with the activity of the alpha-synuclein gene.

"In the middle of this noisy picture of gene expression in blood, we were able to uncover a very clear pattern of activity with these four genes," said Scherzer. "By recognizing that pattern, we then deduced that there must be a switch, or mechanism that was responsible for controlling the activity of these genes."

The next step for researchers was to discover what was controlling the activity of these genes in the blood. For this, Dr. Scherzer and Dr. Schlossmacher, who leads the University of Ottawa research team, turned to Emery Bresnick, an SMPH professor of pharmacology, and an expert in GATA transcription factors. A transcription factor is a dial that turns the activity of genes up or down. Through this collaboration, researchers discovered that the transcription factor, GATA-1, was responsible for controlling the functions of these four genes in the blood and that a relative of GATA-1, the transcription factor GATA-2 â€" which is highly present in the brain regions affected by PD â€" may be responsible for the activity of alpha-synuclein in the brain.

"We were able to show that the GATA-2 transcription factor directly sticks to the alpha-synuclein gene and when GATA-2 was knocked down in dopamine cells, the levels of alpha-synuclein went down as well," said Dr. Schlossmacher.

This discovery illustrates the direct regulation of the gene by GATA factors, but researchers emphasize that further research is needed to understand if this pathway can be used for the development of drug therapies to tailor treatment strategies.

This research was funded by Paul B. Beeson K08AG024816 from the NIA & the American Federation for Aging Research, the American Parkinson Disease Association, Michael J. Fox Foundation, the M.E.M.O. Hoffman Foundation and numerous NIH grants.

Note: This story has been adapted from a news release issued by the Brigham And Women's Hospital

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