Feb. 10, 2016
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.
“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.”
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‘The goal is to find genetic markers that
correlate with environmental
exposures’
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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.
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.
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‘The mutations aren’t so much a risk factor as
they are a cause’
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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.
“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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