Blood-related Genetic Mechanisms Found Important In Parkinson's Disease

http://www.sciencedaily.com/releases...0721173752.htm

ScienceDaily (July 21, 2008) — What does the genetics of blood cells have to do with brain cells related to Parkinson's disease? From an unusual collaboration of neurologists and a pharmacologist comes the surprising answer: Genetic mechanisms at play in blood cells also control a gene and protein that cause Parkinson's disease.

The finding, by scientists from the University of Wisconsin School of Medicine and Public Health (SMPH), Harvard University-affiliated Brigham and Women's Hospital and the University of Ottawa, may lead to new treatments for the neurological disorder that affects as many as 1.5 million Americans.

The study is published in the Proceedings of the National Academy of Sciences Online Early Edition the week of July 21-25, 2008.

Patients with Parkinson's disease (PD) have elevated levels of the protein called alpha-synuclein in their brains. As the protein clumps, or aggregates, the resulting toxicity causes the death of neurons that produce the brain chemical dopamine. Consequently, nerves and muscles that control movement and coordination are destroyed.

The researchers discovered that the activity of three genes that control the synthesis of heme, the major component of hemoglobin that allows red blood cells to carry oxygen, precisely matched the activity of the alpha-synuclein gene, suggesting a common switch controlling both.

The scientists then found that a protein called GATA-1, which turns on the blood-related genes, was also a major switch for alpha-synuclein expression, and that it induced a significant increase in alpha-synuclein protein. Finally, they demonstrated that a related protein -- GATA-2 -- was expressed in PD-vulnerable brain cells and directly controlled alpha-synuclein production.

"Very little was known previously about what turns on alpha-synuclein in brain cells and causes variations in its expression," says Emery Bresnick, a UW-Madison professor of pharmacology who is an expert on GATA factors and their functions in blood. "Understanding how GATA factors work in the brain may provide fundamental insights into the biology of Parkinson's disease."

The new knowledge also may allow scientists to design therapies that keep alpha-synuclein levels within the normal range.

"Simply lowering alpha-synuclein levels by 40 percent may be enough to treat some forms of Parkinson's disease," says Dr. Clemens Scherzer of Harvard. "So far, researchers have focused on ways to get rid of too much 'bad' alpha-synuclein in Parkinson patients' brains. Now we will be able to tackle the problem from the production site, and search for new therapies that lower alpha-synuclein production up front."

Scherzer and Dr. Michael Schlossmacher, now at Ottawa, had independently analyzed the blood of PD patients and controls in a search for genes that were active in the disease. They both were surprised to notice large amounts of alpha-synuclein in the blood. To understand what it was doing there, Scherzer's group used gene chip data to see whether any of the thousands of genes active in blood were linked to alpha-synuclein. They found a gene expression pattern composed of alpha-synuclein and the heme genes, one of which Bresnick had previously shown to be a direct GATA-1 target gene.

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