Parkinson's disease is one of the most common neurodegenerative
diseases, affecting about one percent of all people over the age of 65. It is characterized
by rigidity, bradykinesia (reduced movement) and tremors, which are caused by
the progressive degeneration of dopamine-containing neurons in a brain region
called the substantia nigra. Another characteristic feature of the disease is
that the brains of Parkinson's patients contain microscopic protein deposits,
known as Lewy bodies. Although some cases of Parkinson's disease can be attributed
to genetic risk factors, the majority of cases are still unexplained; these so-called
"sporadic" cases have been proposed to result from environmental factors. In the
December issue of Nature Neuroscience, Tim Greenamyre and colleagues at Emory University in Atlanta, Georgia,
show that rotenone, a commonly used organic pesticide, can induce the major features
of Parkinson's disease in rats. These results not only provide a new animal model
for testing potential treatments, they also support the idea that chronic exposure
to environmental pesticides may contribute to the incidence of Parkinson's disease
in humans.

Before this study, the most realistic animal model of Parkinson's disease
was the so-called MPTP model, in which mice or monkeys are treated with a drug
known as 1,2,3,6-tetrahydropyridine (MPTP). This model originates from the early
1980s, when a number of heroin addicts developed sudden and irreversible symptoms
of Parkinsonism after injecting themselves with an illicit drug preparation
contaminated by MPTP. The reason for the toxic effect is that MPTP (or more
strictly, its derivative MPP+) inhibits one of the enzymes in mitochondria,
intracellular organelles that provide the cell with energy.

Rotenone, like many other pesticides, inhibits the same mitochondrial enzyme
(called complex I) as MPP+, and so Greenamyre and colleagues hypothesized that
chronic treatment with low levels of rotenone might produce Parkinsonian symptoms
in rats. They administered rotenone intravenously over a period of several weeks,
and observed gradual degeneration of the dopamine neurons, accompanied by behavioral
features of Parkinsonism and the formation of structures that closely resemble
Lewy bodies. A likely explanation, as yet untested, is that rotenone acts by
causing the mitochondria to produce free radicals, reactive chemicals that produce
oxidative damage in a variety of contexts and have been implicated in many human
degenerative diseases.

Rotenone is a naturally occurring pesticide, and it is widely used both as
an insecticide and as a method for killing fish (as part of water management
programs). It is considered relatively benign compared to many other pesticides.
Although the new study does not prove that rotenone causes Parkinsonism in humans,
it is likely to raise new questions about rotenone's safety. More generally,
it lends credence to the idea that chronic exposure to environmental toxins,
including pesticides, may contribute to the incidence of the disease. The main
risk factor for Parkinson's disease is age, and it has also been claimed, more
controversially, that the disease is associated with living in rural environments.
Determining to what extent pesticide exposure can account for Parkinsonism will
require a great deal of further work. The present findings, however, are consistent
with the idea that chronic exposure to low levels of environmental toxin may
cause cumulative damage to the brain's dopamine system, eventually leading to
the clinical symptoms of the disease. (From Nature Neuroscience press release.)

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