Animal Model Of Parkinson's Disease Reveals Striking Sensitivity To Common Environmental Toxins

The work is reported in Current Biology by two independent groups, oneled by Nancy Bonini of the University of Pennsylvania and the HowardHughes Medical Institute, and the other led by Kyung-Tai Min of theNINDS branch of the U.S. National Institutes of Health.

Parkinson's disease occurs both sporadically and as a result ofinheritance of single gene mutations. One of the most commonneurodegenerative disorders, it is associated with the progressive andselective loss of a specific population of neurons in the brain, thedopaminergic neurons of the substantia nigra pars compacta . Exposureto several common environmental toxins, thought to injure neuronsthrough oxidative damage, has been shown to be associated with sporadicforms of Parkinson's disease. During the past decade, researchers havealso made remarkable progress in identifying genes responsible forinherited forms of Parkinson's disease, with the expectation thatunderstanding the function of these genes will elucidate mechanismsbehind sporadic Parkinson's disease. Past work had shown that one formof familial Parkinson's disease results from a loss of function of agene called DJ-1.

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

Bonini and colleagues showed that flies lacking both forms of DJ-1activity are normal under standard conditions. However, upon exposureto 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. Thesefindings suggest that loss of DJ-1 function leads to an increasedsensitivity to chemical agents that cause oxidative damage.

Min and his colleagues found that loss of function of one form of flyDJ-1, DJ-1b, caused a compensatory boost in expression of the otherform of the gene, DJ-1a. These flies, lacking DJ-1a function but havingincreased DJ-1a activity, showed extended survival of dopaminergicneurons and resistance to oxidative stress caused by the chemicalparaquat, but at the same time they also exhibited acute sensitivity tohydrogen peroxide treatment. The results showed that overexpression ofDJ-1a in dopaminergic neurons is sufficient to confer protectionagainst paraquat insult.

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

The researchers include Marc Meulener, Cecilia E. Armstrong-Gold andNancy M. Bonini of the University of Pennsylvania in Philadelphia, PA;Alexander J. Whitworth and Leo J. Pallanck of the University ofWashington School of Medicine in Seattle, WA; Patrizia Rizzu and PeterHeutink of the VU University Medical Center in Amsterdam, TheNetherlands; and Paul D. Wes of Elan Pharmaceuticals in South SanFrancisco, CA. This work was supported by a neurodegeneration traininggrant from the University of Pennsylvania, the Measey Foundation, and aNational Research Service Award (National Institute of NeurologicalDisorders and Stroke) (to M.M.), the NIA (to N.M.B.), and a grant fromthe National Institutes of Health (to L.J.P.).

Meulener et al.: "Drosophila DJ-1 mutants are selectively sensitive toenvironmental toxins associated with Parkinson's disease" Publishing inCurrent Biology, Vol. 15, pages 1572–1577, September 6, 2005. DOI10.1016/j.cub.2005.07.064 www.current-biology.com