Mar. 7, 2007 Researchers at The University of Alabama are offering clues as to why some people appear to have a higher risk of developing Parkinson’s disease following exposure to a widely used chemical weed killer.
The research, publishing in the March 7 edition of the Journal of Neuroscience, pinpoints three genes within animal models which influence how susceptible they are to developing a Parkinson’s disease-like movement disorder, said Dr. Janis O’Donnell, a co-author of the research and a professor of biological sciences at The University of Alabama.
“We found these genes do affect how susceptible these individuals are,” O’Donnell said. “Our hope is we can use this observation to discover other genes that might be influencing how these models, or human beings, might be more or less susceptible to these toxic agents.”
The research focused on select genes that influence dopamine synthesis and the release of dopamine from brain cells. The genes identified include those that regulate tetrahydrobiopterin, a compound that is required to make dopamine, as well as those involved directly in dopamine synthesis.
O’Donnell, and current and former students and post-doctoral researchers working in a UA laboratory with her, studied these genes following the animal model’s exposure to the chemical paraquat, an herbicide commonly used throughout the world.
Previous studies have shown elevated Parkinson’s rates within particular agricultural communities. “It was thought that paraquat might be the causative agent,” O’Donnell said, “because the chemical structure of paraquat looks a lot like dopamine, and perhaps it might confuse the cells. But not everybody that lives in these communities gets Parkinson’s. What is it that’s different about different individuals that would alter their susceptibility?”
The answer now appears, at least in part, to lie within these genes identified by the UA researchers.
O’Donnell and her colleagues use fruit flies, known in biological circles by their scientific name, Drosophila melanogaster, in their research. Flies share with humans, and other mammals, many biochemical similarities, particularly in regard to chemicals produced within their brain cells.
Within the fly’s brain is a distinct type of neurotransmitter, dopamine. Each fly has about 200 neurons within its brain that produce dopamine. The human brain, by contrast, has billions of neurons. The simplicity of the fly’s brain lends itself to manageable tracing of experimental impacts on specific neurons. Yet, there are enough similarities in these animals to make them an acceptable model for studying human disease.
“The flies have dopamine neurons, and these dopamine neurons function much like they do in higher organisms,” O’Donnell said. “Dopamine controls your movement, and it controls the fly’s movement. One of the reasons we study the dopamine pathways in the flies is because the genes involved in this process, the proteins involved, the enzymes that make these chemicals, are virtually identical in human beings and in fruit flies.”
In Parkinson’s disease, a movement disorder affecting some 1 million Americans, neurons in the brain that make dopamine die. Recently, genes associated with some cases of Parkinson’s have been identified, but the root cause of most Parkinson’s disease is not understood. The disease is characterized by rigid and tremoring limbs, difficulty in movement, and impaired reflexes.
Using a specialized microscope, the UA researchers analyzed the flies’ brains after the models had ingested low concentrations of paraquat. Within 12 hours, dopamine neurons within particular regions of the brain began dying. Within 24 hours, many of the dopamine neurons were gone.
“Part of our study was to show that it seems to be, initially at least, specifically those neurons that paraquat impacts and not that it’s just a generic cell killer. Later, all kinds of cells are impacted.”
Visual observations of the flies also revealed paraquat’s impact. After ingesting paraquat, the flies, as video evidence shows, began to tremor. They moved slowly, if at all. “These animals are developing symptoms that almost precisely parallel most of the symptoms that doctors find in Parkinson’s patients.”
That wasn’t the only parallel. “Men seem to be about twice as susceptible to Parkinson’s disease, as women are,” O’Donnell said. “We were amazed to find that we see exactly the same effect in male fruit flies. The male fruit flies show symptoms earlier and die more rapidly than the females did—which means, perhaps, that we can exploit this system to help us understand why this discrepancy is there. It’s an interesting corollary that surprised us. We didn’t expect that degree of parallel.”
Another surprising find came in how mutating genes impacted the experiment’s results. “Under certain conditions, dopamine can react to the extent where it becomes damaging to some of the cell structures. We think of these dopamine neurons as being more susceptible to this kind of damage, called oxidative damage, because they have more dopamine.”
However, in the study, flies with a mutated gene that made too little dopamine became very susceptible to paraquat while mutants who made too much dopamine were resistant.
In some cases, flies with a particular mutated gene showed no neuron damage despite ingesting the paraquat.
“That’s exciting because it tells us that perhaps there are ways to exploit this, to identify different ways that people could be treated to help slow down the progress of this disease. By the time you discover a person has Parkinson’s disease, they have lost so many neurons, it’s almost impossible to reverse the trend. If you could predict it in advance, perhaps there would be some sort of therapy that could be applied to help protect those individuals.”
The lead author of the study, parts of which were initially funded by NASA and the National Institutes of Health, is Dr. Anathbandhu “Andy” Chaudhuri, a former post-doctoral researcher at UA. Current UA graduate students Kevin Bowling, Hakeem Lawal and Arati Inamdar are co-authors, as are UA graduates Christopher Funderburk and Zhe Wang.
“The importance to me,” O’Donnell said of the study, “is that it is setting the stage for a more detailed study of how all these genes interact together. There is so much that we don’t know yet about how the genes are functioning in particular parts of the brain and how they interact with the environment. We’re interested to know if there are other important genes that are helping to regulate this, and, if there are, those would be possible targets that human geneticists would be interested in investigating.”
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