The Drosophila carbonyl reductase sniffer prevents oxidative stress-induced neurodegeneration.
A growing body of evidence suggests that oxidative stress is a common underlying mechanism in the pathogenesis of neurodegenerative disorders such as Alzheimer's, Huntington's, Creutzfeld-Jakob and Parkinson's diseases. Despite the increasing number of reports finding a causal relation between oxidative stress and neurodegeneration, little is known about the genetic elements that confer protection against the deleterious effects of oxidation in neurons. We have isolated and characterized the Drosophila melanogaster gene sniffer, whose function is essential for preventing age-related neurodegeneration. In addition, we demonstrate that oxidative stress is a direct cause of neurodegeneration in the Drosophila central nervous system and that reduction of sniffer activity leads to neuronal cell death. The overexpression of the gene confers neuronal protection against oxygen-induced apoptosis, increases resistance of flies to experimental normobaric hyperoxia, and improves general locomotor fitness. Sniffer belongs to the family of short-chain dehydrogenase/reductase (SDR) enzymes and exhibits carbonyl reductase activity. This is the first in vivo evidence of the direct and important implication of this enzyme as a neuroprotective agent in the cellular defense mechanisms against oxidative stress.
Botella
Jose A
JA
Institute of Zoology, University of Regensburg, Universitaetsstrasse 31, D-93040 Regensburg, Germany.
Ulschmid
Julia K
JK
Gruenewald
Christoph
C
Moehle
Christoph
C
Kretzschmar
Doris
D
Becker
Katja
K
Schneuwly
Stephan
S
D000367:Age Factors; D000429:Alcohol Oxidoreductases / Q000235:genetics* / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D001921:Brain / Q000503:physiopathology; D029721:Drosophila Proteins / Q000235:genetics* / Q000502:physiology; D004331:Drosophila melanogaster / Q000235:genetics* / Q000502:physiology; D004591:Electrophoresis, Polyacrylamide Gel; D015870:Gene Expression; D006651:Histocytochemistry; D020287:In Situ Nick-End Labeling; D008969:Molecular Sequence Data; D009410:Nerve Degeneration / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D010100:Oxygen; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment
D029721:Drosophila Proteins; C487696:sni protein, Drosophila; D000429:Alcohol Oxidoreductases; D010100:Oxygen