For several years, neurologists at UCLA have been
building a case that a link exists between
pesticides 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.
Now, UCLA researchers have discovered a link between
Parkinson's and another pesticide, benomyl, whose
toxicological effects still linger some 10 years
after the chemical was banned by the U.S.
Environmental Protection Agency.
Even more significantly, the 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,
according to Jeff Bronstein, senior author of the
study and a professor of neurology at UCLA, and his
colleagues. Benomyl exposure, they say, starts a
cascade of cellular events that may lead to
Parkinson's. 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 concerning
benomyl may be generalized to all Parkinson's
patients. Developing new drugs to protect ALDH
activity, they say, may eventually help slow the
progression of the disease, whether or not an
individual has been exposed to pesticides. The
research is published in the current online edition
of Proceedings of the National Academy of Sciences.
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
manifest themselves, more than half of these neurons,
known as dopaminergic neurons, have already been
lost.
While researchers have identified certain genetic
variations that cause an inherited form of
Parkinson's, only a small fraction of the disease
can be blamed on genes, said the study's first
author, Arthur G. Fitzmaurice, a postdoctoral
scholar in Bronstein's laboratory.
"As a result, environmental factors almost certainly
play an important role in this disorder,"
Fitzmaurice said. "Understanding the relevant
mechanisms—particularly what causes the selective
loss of dopaminergic neurons—may provide important
clues to explain how the disease develops."
Benomyl was widely used in the U.S. 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.
The researchers wanted to explore whether there was
a relationship between benomyl and Parkinson's,
which would demonstrate the possibility of
long-lasting toxicological effects from pesticide
use, even a decade after chronic exposure. But
because a direct causal relationship between the
pesticide and Parkinson's can't be established by
testing humans, the investigators sought to
determine if exposure in experimental models 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, 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. 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. (See
UCLA research using "molecular tweezers" to break up
these toxic aggregations.)
The identification of ALDH activity now gives
researchers another target to focus on in trying to
stop this disease. "We've known that in animal
models and cell cultures, agricultural pesticides
trigger a neurodegenerative process that leads to
Parkinson's," said Bronstein, who directs the UCLA
Movement Disorders Program. "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."
For more information
Aldehyde dehydrogenase inhibition as a pathogenic
mechanism in Parkinson disease
(MDN)
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