Animal model of Parkinson’s disease reveals striking sensitivity to common environmental toxins
In findings that support a relationship between agricultural chemicals and Parkinsons disease, two groups of researchers have found new evidence that loss of DJ-1, a gene known to be linked to inherited Parkinsons 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 Parkinsons 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.
Parkinsons 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 Parkinsons disease. During the past decade, researchers have also made remarkable progress in identifying genes responsible for inherited forms of Parkinsons disease, with the expectation that understanding the function of these genes will elucidate mechanisms behind sporadic Parkinsons disease. Past work had shown that one form of familial Parkinsons 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 Parkinsons disease situation by deleting one or both forms of DJ-1 from the flys 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 Parkinsons 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 Parkinsons disease.
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