Interaction of Genetic and Environmental Factors in aDrosophilaParkinsonism Model

Journal of Neuroscience - Tập 27 Số 10 - Trang 2457-2467 - 2007
Anathbandhu Chaudhuri1, Kevin M. Bowling2,3,4,5,6, Christopher D. Funderburk2,3,4,5,6, Hakeem O. Lawal2,3,4,5,6, Arati A. Inamdar2,3,4,5,6, Zhe Wang2,3,4,5,6, Janis M. O’Donnell2,3,4,5,6
1Department of Biological Sciences University of Alabama Tuscaloosa Alabama 35487-0344 USA
2Department of Biological Sciences, University of Alabama, Tuscaloosa, AL 35487-0344.
3Department of Biological Sciences, University of Alabama, Tuscaloosa, Alabama 35487-0344
4Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800. C.
5Emory University School of Medicine, Center for Behavioral Neuroscience, At-lanta, GA 30329. Z.
6Stower Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110.

Tóm tắt

Catastrophic loss of dopaminergic neurons is a hallmark of Parkinson's disease. Despite the recent identification of genes associated with familial parkinsonism, the etiology of most Parkinson's disease cases is not understood. Environmental toxins, such as the herbicide paraquat, appear to be risk factors, and it has been proposed that susceptibility is influenced by genetic background. The genetic model organismDrosophilais an advantageous system for the identification of genetic susceptibility factors. Genes that affect dopamine homeostasis are candidate susceptibility factors, because dopamine itself has been implicated in neuron damage. We find that paraquat can replicate a broad spectrum of parkinsonian behavioral symptoms inDrosophilathat are associated with loss of specific subsets of dopaminergic neurons. In parallel with epidemiological studies that show an increased incidence of Parkinson's disease in males, maleDrosophilaexhibit paraquat symptoms earlier than females. We then tested the hypothesis that variation in dopamine-regulating genes, including those that regulate tetrahydrobiopterin, a requisite cofactor in dopamine synthesis, can alter susceptibility to paraquat-induced oxidative damage.Drosophilamutant strains that have increased or decreased dopamine and tetrahydrobiopterin production exhibit variation in susceptibility to paraquat. Surprisingly, protection against the neurotoxicity of paraquat is conferred by mutations that elevate dopamine pathway function, whereas mutations that diminish dopamine pools increase susceptibility. We also find that loss-of-function mutations in a negative regulator of dopamine production,Catecholamines-up, delay the onset of neurological symptoms, dopaminergic neuron death, and morbidity during paraquat exposure but confer sensitivity to hydrogen peroxide.

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Journal of Neuroscience

Tập 27 Số 10

2457-2467

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