Increased glutathione S-transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease

Loss-of-function mutations of the parkin gene are a major cause of early-onset parkinsonism. To explore the mechanism by which loss of parkin function results in neurodegeneration, we are using a genetic approach in Drosophila. Here, we show that Drosophila parkin mutants display degeneration of a s...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 22; pp. 8024 - 8029
Main Authors:	Whitworth, A.J, Theodore, D.A, Greene, J.C, Benes, H, Wes, P.D, Pallanck, L.J
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 31-05-2005 National Acad Sciences
Subjects:	Alleles animal disease models Animals Biological Sciences Brain dopaminergic neuron loss Drosophila Drosophila melanogaster Drosophila Proteins - genetics enzyme activity Enzymes Gene Expression genes Genetic mutation Genetic screening glutathione transferase Glutathione Transferase - genetics Glutathione Transferase - metabolism Green Fluorescent Proteins Insects Interneurons - metabolism Interneurons - pathology Locomotion - physiology Microscopy, Confocal modifiers (genes) mutants Mutation Mutation - genetics Nerve Degeneration - genetics neurodegeneration Neurons Oxidative stress parkin gene Parkinson disease Parkinson Disease - enzymology Parkinson Disease - genetics Parkinson's disease pathogenesis Phenotypes Transgenes Ubiquitin-Protein Ligases Viability
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Summary:	Loss-of-function mutations of the parkin gene are a major cause of early-onset parkinsonism. To explore the mechanism by which loss of parkin function results in neurodegeneration, we are using a genetic approach in Drosophila. Here, we show that Drosophila parkin mutants display degeneration of a subset of dopaminergic (DA) neurons in the brain. The neurodegenerative phenotype of parkin mutants is enhanced by loss-of-function mutations of the glutathione S-transferase S1 (GstS1) gene, which were identified in an unbiased genetic screen for genes that modify parkin phenotypes. Furthermore, overexpression of GstS1 in DA neurons suppresses neurodegeneration in parkin mutants. Given the previous evidence for altered glutathione metabolism and oxidative stress in sporadic Parkinson's disease (PD), these data suggest that the mechanism of DA neuron loss in Drosophila parkin mutants is similar to the mechanisms underlying sporadic PD. Moreover, these findings identify a potential therapeutic approach in treating PD.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 This paper was submitted directly (Track II) to the PNAS office. Abbreviations: PD, Parkinson's disease; DA, dopaminergic; GstS1, glutathione S-transferase S1; ARJP, autosomal recessive juvenile parkinsonism; TH, tyrosine hydroxylase; PPL, protocerebral posterior lateral; UAS, upstream activating sequence. To whom correspondence may be sent at the present address: Department of Biomedical Sciences, University of Sheffield, Sheffield S10 2TN, United Kingdom. E-mail: a.whitworth@sheffield.ac.uk. ∥To whom correspondence may be addressed. E-mail: pallanck@gs.washington.edu. D.A.T. and P.D.W. are employees of and have personal financial interests in Elan Pharmaceuticals. Funding for part of the research conducted in this study was provided by Elan. Edited by Richard D. Palmiter, University of Washington School of Medicine, Seattle, WA, and approved April 20, 2005
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.0501078102