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The Journal of Neuroscience, January 9, 2008, 28(2):465-472; doi:10.1523/JNEUROSCI.4778-07.2008

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Neurobiology of Disease
Induction of the Phase II Detoxification Pathway Suppresses Neuron Loss in Drosophila Models of Parkinson's Disease

Kien Trinh,1 Katherine Moore,1 Paul D. Wes,4 Paul J. Muchowski,3 Joyoti Dey,2 Laurie Andrews,1 and Leo J. Pallanck1

1Department of Genome Sciences and 2Molecular and Cellular Biology Program, University of Washington, Seattle, Washington 98195, 3Gladstone Institute of Neurological Disease and Departments of Biochemistry and Biophysics, and Neurology, University of California, San Francisco, San Francisco, California 94158, 4Elan Pharmaceuticals, South San Francisco, California 94080

Correspondence should be addressed to Dr. Leo J. Pallanck, University of Washington, 1705 NE Pacific Street, Foege S-443E, Box 355065, Seattle, WA 98195-5065. Email: pallanck{at}u.washington.edu

{alpha}-Synuclein aggregates are a common feature of sporadic Parkinson's disease (PD), and mutations that increase {alpha}-synuclein abundance confer rare heritable forms of PD. Although these findings suggest that {alpha}-synuclein plays a central role in the pathogenesis of this disorder, little is known of the mechanism by which {alpha}-synuclein promotes neuron loss or the factors that regulate {alpha}-synuclein toxicity. To address these matters, we tested candidate modifiers of {alpha}-synuclein toxicity using a Drosophila model of PD. In the current work, we focused on phase II detoxification enzymes involved in glutathione metabolism. We find that the neuronal death accompanying {alpha}-synuclein expression in Drosophila is enhanced by loss-of-function mutations in genes that promote glutathione synthesis and glutathione conjugation. This neuronal loss can be overcome by genetic or pharmacological interventions that increase glutathione synthesis or glutathione conjugation activity. Moreover, these same pharmacological agents suppress neuron loss in Drosophila parkin mutants, a loss-of-function model of PD. Our results suggest that oxidative stress is a feature of {alpha}-synuclein toxicity and that induction of the phase II detoxification pathway represents a potential preventative therapy for PD.

Key words: {alpha}-synuclein; dopamine; Drosophila; synucleinopathy; glutathione; glutathione S-transferase

Received Jan. 22, 2007; accepted Nov. 19, 2007.

Correspondence should be addressed to Dr. Leo J. Pallanck, University of Washington, 1705 NE Pacific Street, Foege S-443E, Box 355065, Seattle, WA 98195-5065. Email: pallanck{at}u.washington.edu






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