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

Kien Trinh,K. Moore,P. Wes,P. Muchowski,Joyoti Dey,Laurie A. Andrews,L. Pallanck

Published 2008 in Journal of Neuroscience

ABSTRACT

α-Synuclein aggregates are a common feature of sporadic Parkinson's disease (PD), and mutations that increase α-synuclein abundance confer rare heritable forms of PD. Although these findings suggest that α-synuclein plays a central role in the pathogenesis of this disorder, little is known of the mechanism by which α-synuclein promotes neuron loss or the factors that regulate α-synuclein toxicity. To address these matters, we tested candidate modifiers of α-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 α-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 α-synuclein toxicity and that induction of the phase II detoxification pathway represents a potential preventative therapy for PD.

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