Animal model of Parkinson's disease reveals striking sensitivity to
common environmental toxins

6-Sep-2005(EurekAlert) - In findings that support a relationship
between agricultural chemicals and Parkinson's disease, two groups of
researchers have found new evidence that loss of DJ-1, a gene known
to be linked to inherited Parkinson's disease, leads to striking
sensitivity to the herbicide paraquat and the insecticide rotenone.
The two studies were performed with the fruit fly Drosophila, a
widely used model organism for studies of human disease, and shed new
light on biological connections between inherited and sporadic forms
of Parkinson's disease.
The work is reported in Current Biology by two independent groups,
one led by Nancy Bonini of the University of Pennsylvania and the
Howard Hughes Medical Institute, and the other led by Kyung-Tai Min
of the NINDS branch of the U.S. National Institutes of Health.

Parkinson's disease occurs both sporadically and as a result of
inheritance of single gene mutations. One of the most common
neurodegenerative disorders, it is associated with the progressive
and selective loss of a specific population of neurons in the brain,
the dopaminergic neurons of the substantia nigra pars compacta .

Exposure to several common environmental toxins, thought to injure
neurons through oxidative damage, has been shown to be associated
with sporadic forms of Parkinson's disease. During the past decade,
researchers have also made remarkable progress in identifying genes
responsible for inherited forms of Parkinson's disease, with the
expectation that understanding the function of these genes will
elucidate mechanisms behind sporadic Parkinson's disease. Past work
had shown that one form of familial Parkinson's disease results from
a loss of function of a gene called DJ-1.

The fruit fly possesses two versions of the DJ-1 gene, and in the new
work, the researchers simulated the human Parkinson's disease
situation by deleting one or both forms of DJ-1 from the fly's DNA.

Bonini and colleagues showed that flies lacking both forms of DJ-1
activity are normal under standard conditions. However, upon exposure
to widely used agricultural agents, including paraquat and rotenone,
previously associated with the sporadic form of Parkinson's disease,
the flies show strikingly increased sensitivity and death. These
findings suggest that loss of DJ-1 function leads to an increased
sensitivity to chemical agents that cause oxidative damage.

Min and his colleagues found that loss of function of one form of fly
DJ-1, DJ-1b, caused a compensatory boost in expression of the other
form of the gene, DJ-1a. These flies, lacking DJ-1â function but
having increased DJ-1á activity, showed extended survival of
dopaminergic neurons and resistance to oxidative stress caused by the
chemical paraquat, but at the same time they also exhibited acute
sensitivity to hydrogen peroxide treatment. The results showed that
overexpression of DJ-1a in dopaminergic neurons is sufficient to
confer protection against paraquat insult.

Together, the results from the two studies suggest that Drosophila DJ-
1 genes, and potentially human DJ-1, play critical roles in the
survival of dopaminergic neurons and the response to oxidative
cellular stress. In addition, the studies also highlight DJ-1 as a
potential therapeutic target for the treatment of Parkinson's
disease.