Induction of the phase II detoxification pathway suppresses neuron loss in Drosophila models of Parkinson's disease.
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.
Trinh
Kien
K
Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
Moore
Katherine
K
Wes
Paul D
PD
Muchowski
Paul J
PJ
Dey
Joyoti
J
Andrews
Laurie
L
Pallanck
Leo J
LJ
D000367:Age Factors; D000498:Allyl Compounds; D000818:Animals; D030801:Animals, Genetically Modified; D016923:Cell Death / Q000235:genetics; D004195:Disease Models, Animal; D004220:Disulfides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics; D005978:Glutathione / Q000378:metabolism; D017879:Isothiocyanates; D050217:Metabolic Detoxication, Phase II / Q000502:physiology*; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D009154:Mutation; D009410:Nerve Degeneration / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics
D000498:Allyl Compounds; D004220:Disulfides; D029721:Drosophila Proteins; D017879:Isothiocyanates; D009419:Nerve Tissue Proteins; D013454:Sulfoxides; D013861:Thiocyanates; D051844:alpha-Synuclein; C028009:diallyl disulfide; D014446:Tyrosine 3-Monooxygenase; C016766:sulforaphane; D005978:Glutathione