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 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.
Whitworth
Alexander J
AJ
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA. a.whitworth@sheffield.ac.uk
Theodore
Dorothy A
DA
Greene
Jessica C
JC
Benes
Helen
H
Wes
Paul D
PD
Pallanck
Leo J
LJ
D000818:Animals; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics*; D015870:Gene Expression; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D007395:Interneurons / Q000378:metabolism / Q000473:pathology*; D008124:Locomotion / Q000502:physiology; D018613:Microscopy, Confocal; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics*; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases
D029721:Drosophila Proteins; D049452:Green Fluorescent Proteins; D044767:Ubiquitin-Protein Ligases; D005982:Glutathione Transferase; C487430:park protein, Drosophila