�What does the genetics of blood cells receive to do with brain cells related to Parkinson's disease? From an unusual collaboration of neurologists and a pharmacologist comes the surprising serve: Genetic mechanisms at run in blood cells also control a gene and protein that cause Parkinson's disease.
The determination, 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 jillion 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 chemic dopamine. Consequently, nerves and muscles that control movement and coordination are destroyed.
The researchers observed that the activity of three genes that control the synthetic thinking of haemitin, the major component of hemoglobin that allows red River blood cells to convey oxygen, exactly matched the activity of the alpha-synuclein gene, suggesting a common switch controlling both.
The scientists then establish that a protein called GATA-1, which turns on the cognate genes, was also a major switch for alpha-synuclein expression, and that it induced a significant growth in alpha-synuclein protein. Finally, they demonstrated that a related protein - GATA-2 - was expressed in PD-vulnerable encephalon 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 technical on GATA factors and their functions in blood. "Understanding how GATA factors work in the brain may bring home the bacon fundamental insights into the biology of Parkinson's disease."
The new cognition also crataegus laevigata allow scientists to plan therapies that keep alpha-synuclein levels within the normal range.
"Simply lowering alpha-synuclein levels by 40 percent whitethorn be enough to regale some forms of Parkinson's disease," says Dr. Clemens Scherzer of Harvard. "So far, researchers have focussed on shipway 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 lour 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 factor chip information to learn whether whatever of the thousands of genes alive in blood were linked to alpha-synuclein. They establish a factor expression rule composed of alpha-synuclein and the heme genes, ane of which Bresnick had previously shown to be a train GATA-1 quarry gene.
The neurologists contacted Bresnick. The UW group quickly determined that GATA-1 at once activated the alpha-synuclein factor, and that finding lED the collaborators to discover that GATA-2 is expressed in regions of the brain that are relevant to PD.
"We all were excited because we completed that GATA-2 was active in the relevant mastermind regions, and so on that point could be a connection," says Bresnick. Together the researchers set out to examine whether common mechanisms activated alpha-synuclein transcription in both the blood and nerve cells.
The studies showed that GATA-1 and GATA-2 proteins find the alpha-synuclein gene, sting to it and then directly control it.
"This is not an indirect pathway; it is direct regulation of the gene," says Bresnick. "This directness provides the simplest scenario for creating a therapeutic strategy."
Bresnick, Schlossmacher and Scherzer are working with geneticists to see if possible abnormalities in the GATA-2 cistron may exist in PD patients, stimulating more production of alpha-syinuclein.
"The discovery of the connectedness between GATA proteins and the alpha-synuclein gene is like finding a long-sought-after molecular switch," says Schlossmacher. "We were very rosy to line up in Emery Bresnick's team the ideal partner in this endeavor."
The family of GATA factors consists of six members, and some of them, beyond GATA-2, may likewise be influencing alpha-synuclein construction in the brain, adds Schlossmacher.
"Identifying these would further add to the complexness of regulating the production of the 'bad player' in Parkinson's disease," he says.
Says Bresnick, "The $10 million query will be: Does deregulation of the GATA mechanics in man lead to alpha-synuclein overrun and Parkinson's disease?"
Source: Dian Land
University of Wisconsin-Madison
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