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

TitleIncreased glutathione S-transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease.
Publication TypeJournal Article
Year of Publication2005
AuthorsWhitworth, AJ, Theodore, DA, Greene, JC, Benes, H, Wes, PD, Pallanck, LJ
JournalProc Natl Acad Sci U S A
Volume102
Issue22
Pagination8024-9
Date Published2005 May 31
ISSN0027-8424
KeywordsAnimals, Drosophila, Drosophila Proteins, Gene Expression, Glutathione Transferase, Green Fluorescent Proteins, Interneurons, Locomotion, Microscopy, Confocal, Mutation, Nerve Degeneration, Parkinson Disease, Ubiquitin-Protein Ligases
Abstract

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.

DOI10.1073/pnas.0501078102
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
Citation Key10.1073/pnas.0501078102
PubMed ID15911761
PubMed Central IDPMC1142368
Grant List1R01NS41780-01 / NS / NINDS NIH HHS / United States