Extended lifespan of Drosophila parkin mutants through sequestration of redox-active metals and enhancement of anti-oxidative pathways.
The mechanisms underlying neuron death in Parkinson's disease are unknown, but both genetic defects and environmental factors are implicated in its pathogenesis. Mutations in the parkin gene lead to autosomal recessive juvenile Parkinsonism (AR-JP). Here we report that compared to control flies, Drosophila lacking parkin show significantly reduced lifespan but no difference in dopamine neuron numbers when raised on food supplemented with environmental pesticides or mitochondrial toxins. Moreover, chelation of redox-active metals, anti-oxidants and overexpression of superoxide dismutase 1 all significantly reversed the reduced longevity of parkin-deficient flies. Finally, parkin deficiency exacerbated the rough eye phenotype of Drosophila caused by overexpression of the copper importer B (Ctr1B). Taken together, our results demonstrate an important function of parkin in the protection against redox-active metals and pesticides implicated in the etiology of Parkinson's disease. They also corroborate that oxidative stress, perhaps as a consequence of mitochondrial dysfunction, is a major determinant of morbidity in parkin mutant flies.
Saini
Nidhi
N
Institute for Molecular Life Sciences, University of Zürich, Winterthurerstrasse 190, CH-8051 Zürich, Switzerland.
Oelhafen
Sandra
S
Hua
Haiqing
H
Georgiev
Oleg
O
Schaffner
Walter
W
Büeler
Hansruedi
H
D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000172:deficiency* / Q000235:genetics; D004331:Drosophila melanogaster / Q000235:genetics*; D008136:Longevity / Q000187:drug effects / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics
D029721:Drosophila Proteins; D044767:Ubiquitin-Protein Ligases; C487430:park protein, Drosophila