A new study on the link between another pesticides and Parkinson’s disease may lead to new treatments for individuals who suffer from the debilitating condition. For several years, UCLA researchers have been studying a link between pesticide exposure and Parkinson’s disease. To date, paraquat, maneb, and ziram (common chemicals sprayed in California’s Central Valley and elsewhere) have been tied to increases in the disease, not only among farmworkers but in individuals who simply lived or worked near fields and likely inhaled drifting particles. On January 3, the researchers reported that they have found a link between Parkinson’s disease and another pesticide, benomyl. They published their findings in the current online edition of Proceedings of the National Academy of Sciences.
Benomyl was widely used in the United States for three decades until toxicological evidence revealed it could potentially lead to liver tumors, brain malformations, reproductive effects and carcinogenesis. It was banned in 2001 by the U.S. Environmental Protection Agency; however, its toxicological effects still linger. In addition, the UCLA investigators note that their research suggests that the damaging series of events set in motion by benomyl may also occur in people with Parkinson’s disease who were never exposed to the pesticide.
Senior author Jeff Bronstein, a professor of neurology at UCLA, and his colleagues note that benomyl exposure initiates a cascade of cellular events that may lead to Parkinson’s disease. The pesticide prevents an enzyme called ALDH (aldehyde dehydrogenase) from keeping a lid on DOPAL, a toxin that naturally occurs in the brain. When left unchecked by ALDH, DOPAL accumulates, damages neurons and increases an individual’s risk of developing Parkinson’s.
The investigators believe their findings regarding benomyl may be generalized to all Parkinson’s disease patients. They explain that developing new drugs to protect ALDH activity may eventually help slow the progression of the disease, whether or not an individual has been exposed to pesticides.
Parkinson’s disease is a debilitating neurodegenerative disorder that affects millions worldwide. Its symptoms, including tremor, rigidity, and slowed movements and speech, increase with the progressive degeneration of neurons, primarily in a part of the mid-brain called the substantia nigra. This area normally produces dopamine, a neurotransmitter that allows cells to communicate, and damage to the mid-brain has been linked to the disease. Usually, by the time Parkinson’s symptoms become apparent, more than half of these neurons, known as dopaminergic neurons, have already been lost. Researchers have identified certain genetic variations that cause an inherited form of Parkinson’s disease, only a small fraction of the disease can be blamed on genes, explained the study’s first author, Arthur G. Fitzmaurice, a postdoctoral scholar in Dr. Bronstein’s laboratory. He explained, “As a result, environmental factors almost certainly play an important role in this disorder. Understanding the relevant mechanisms — particularly what causes the selective loss of dopaminergic neurons — may provide important clues to explain how the disease develops.”
The researchers explored whether there was a relationship between benomyl and Parkinson’s. If a a relationship was proven to exist, it would demonstrate the possibility of long-lasting toxicological effects from pesticide use, even a decade after chronic exposure. However, because a direct causal relationship between the pesticide and Parkinson’s disease cannot be established by testing humans, the investigators used experimental models to determine whether benomyl exposure could duplicate some of the pathologic features of the disease.
They first tested the effects of benomyl in cell cultures and confirmed that the pesticide damaged or destroyed dopaminergic neurons. Next, they tested the pesticide in a zebrafish model of the disease. This freshwater fish is commonly used in research because it is easy to manipulate genetically, it develops rapidly and it is transparent; thus, making the observation and measurement of biological processes much easier. By using a fluorescent dye and counting the neurons, the researchers discovered there was significant neuron loss in the fish — but only to the dopaminergic neurons. The other neurons were left unaffected.
Until now, evidence had pointed to one particular culprit, a protein called α-synuclein, in the development of Parkinson’s disease. This protein, common to all Parkinson’s patients, is thought to create a pathway to the disease when it binds together in “clumps” and becomes toxic, killing the brain’s neurons.
The identification of ALDH activity now gives researchers another target to focus on in trying to halt the progress of Parkinson’s disease. Dr Bronstein explained, “We’ve known that in animal models and cell cultures, agricultural pesticides trigger a neurodegenerative process that leads to Parkinson’s. And epidemiologic studies have consistently shown the disease occurs at high rates among farmers and in rural populations. Our work reinforces the hypothesis that pesticides may be partially responsible, and the discovery of this new pathway may be a new avenue for developing therapeutic drugs.”
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