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Toxic Triggers: Genes, Pesticides, and Parkinson's Disease
Charles W. Schmidt

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Parkinson's disease is a case study of how genes and environment might interact to cause illness. Both inherited mutations and exposure to chemicals are risk factors, but neither factor explains all cases. Many people who are exposed to chemical toxins regularly during their lives do not develop the disease, while others without any obvious exposure do. And a family history of the disease is a risk factor but does not necessarily mean that one will become ill. Susceptibility for Parkinson's disease, say many researchers, involves combinations of genetic and environmental risk factors, including exposure to manganese, lead, and pesticides.

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"The balance between genetic and environmental factors, of course, will vary among individuals," says Donato Di Monte, of the Parkinson's Institute in Sunnyvale, California. "In some individuals, the greatest risk might come from genetic predisposition, and in others, the risk from environmental insults might be more important."

‘The goal is to find genetic markers that correlate with environmental exposures’

Parkinson's researchers at the University of Washington are investigating the link between specific genes and chemicals. Harvey Checkoway and colleagues are using automatic DNA sequencers to identify variants, or polymorphisms, in genes known to either activate or detoxify chemicals. The researchers then analyze these genes in affected and healthy individuals to determine which polymorphisms may be associated with Parkinson's.

"The goal is to find genetic markers that correlate with environmental exposures," says Checkoway, Professor of Environmental Health at the University of Washington in Seattle. "We're identifying variants in genes of interest and looking for differences between cases and controls." Two of the genes being analyzed are those coding for cytochrome P-450 and monoamine oxidase.

Monoamine oxidase is an enzyme that interests researchers because it tends to be inhibited in smokers, and studies show that smokers are less likely to develop Parkinson's. Furthermore, monoamine oxidase is involved in the degradation of dopamine, a neurotransmitter found in the region of the brain most affected by Parkinson's: the substantia nigra. Dopamine is necessary for normal communication between the brain and muscles, and its loss can lead to tremors, rhythmic motions, and rigidity.

Checkoway's group is funded in part by a grant program entitled "The Role of the Environment in Parkinson's Disease." The program is run by two U.S. agencies—the National Institute of Health Environmental Health Sciences and the National Institute of Neurological Disorders and Stroke—and will spend some $6 million on research projects.

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This area of research builds on new findings that link environmental toxins to Parkinson's. Ranjita Betarbet, of Emory University in Atlanta, Georgia, and colleagues recently found that chronic exposure to the common pesticide rotenone induces the major features of Parkinson's in rats. This is not the first time scientists have used chemicals to produce Parkinson's symptoms in animals. An illicit drug called MTPT, which causes brain damage that affects dopamine levels, has been studied in an animal model for Parkinson's since the 1980s. But unlike MTPT, which is rarely used, rotenone is everywhere—the chemical is among the most common gardening pesticides on the market.

"This is the first example of Parkinson's symptoms in animals treated with an environmentally relevant chemical," says Donato Di Monte, Research Director at the Parkinson's Institute. "It's a major turning point in our understanding of the disease." The research appeared in the December issue of Nature Neuroscience.

‘The mutations aren’t so much a risk factor as they are a cause’

Viewed in the context of gene-environment interactions, the findings in rats are particularly interesting. When the Emory scientists examined the brains of the rotenone-treated rats, they were surprised and pleased to discover spherical clumps of protein in the substantia nigra. Known as Lewy bodies, the clumps are a characteristic feature of Parkinson's disease in humans, but previous efforts to produce them in animals using chemicals have failed. The clumps, or inclusions, consist largely of a protein called alpha synuclein, which has long been associated with inherited forms of Parkinson's disease.

"The alpha synuclein protein is where the environmental and genetic components of the disease come together," says Benoit Giasson, of the Center for Neurodegenerative Disease Research at the University of Pennsylvania. "We think that rotenone can induce oxidative stress, which by some undefined mechanism leads to synuclein inclusions." Giasson co-authored a News & Views piece in the December Nature Neuroscience called "A new link between pesticides and Parkinson's disease."

Researchers discovered years ago that two mutations in alpha synuclein were associated with Parkinson's in a large family from Southern Italy. All 60 members of the Contursi family with Parkinson's on either side of the Atlantic carried these mutations, while the unaffected members did not. Later it was determined that the mutations—one in which alanine is mutated to proline at position 30 and another in which alanine is changed to threonine at position 53—guaranteed the onset of Parkinson's in all patients.

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"The mutations aren't so much a risk factor as they are a cause," explains Giasson. Nevertheless, not all Parkinson's patients carry the mutations. Furthermore, in most patients the Lewy bodies contain a normal form of the protein. According to Di Monte, these findings link alpha synuclein to Parkinson's disease whether or not there is a mutation in the amino acid sequence.

The Emory researchers suggest in their paper that in addition to damaging neurons in the substantia nigra, rotenone may also target DNA and alpha synuclein in ways that cause the protein to aggregate in Lewy bodies. Their data do not clarify the role of inherited mutations in enhancing chemical susceptibility to Parkinson's. But inherited mutations are likely to have played a role, says Todd Sherer, a member of the team, because not every rat in the study developed symptoms. A number of researchers plan to investigate the effects of rotenone and other chemicals in mice bred to express high levels of alpha synuclein.

The findings in rats are consistent with data suggesting that agricultural chemicals are risk factors for Parkinson's in humans. Exposure to herbicides, insecticides, and even 'rural living,' were associated with an elevated risk for Parkinson's in a study by Jay Gorell, of the Henry Ford Health System in Detroit, Michigan, and colleagues in Neurology.

Other researchers, including Karen Marder, of Columbia University in New York, report evidence that gardening may be a risk factor for Parkinson's. Though preliminary, Marder's findings also suggest that the risk for Parkinson's from gardening among Caucasian and Hispanic populations may be higher than among African Americans. "This indicates that genetic and environmental risk factors may differ among ethnic groups," says Marder, who notes that there may be several explanations for the discrepancy.

"Whether African American and Hispanic populations have different rates of Parkinson's has not been established," she says. "It is possible that issues related to the under-diagnosis of disease and access to medical care may be involved. We're investigating those possibilities now."

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Betarbet, R. et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 3, 1301-1306 (December 2000).
Gorell, J.M. et al. The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living. Neurology 50, 1346-1350 (May 1998).

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