13 May 2004

Evidence linking mitochondrial oxidative stress with neurodegeneration has been pouring forth lately (see, for example, ARF related news on Parkinson’s, ARF related news story and ARF related story). But news of novel mechanisms to prevent damaging oxidations has been less than resounding. If you think you smell a rat, don’t worry. Sniffer, a fly gene that prevents oxidative stress-induced neurodegeneration, is here.

In the May 4 Current Biology, Stephan Schneuwly and colleagues at the University of Regensburg, Germany, reveal that fruit flies carrying mutations in sniffer show neurodegeneration and walk sluggishly, and that both problems worsen with age. To investigate the genetic basis for this behavior, first author Jose Botella and colleagues located the P element transposon that causes the phenotype. The element was located in the intron of the sniffer gene and depletes its expression; removal of the P element fully rescued the flies.

Sniffer, it turns out, is a carbonyl reductase, enzymes responsible for reduction of a variety of carbonyl compounds. Their expression has been found to be upregulated in the brains of those with Alzheimer’s disease; see Balcz et al., 2001. (The same study also noted increased expression of alcohol dehydrogenase, another enzyme implicated in oxidative damage; see ARF related news story.)

To assess sniffer’s potential role in controlling oxidative stress, Botella exposed mutant flies to hyperoxia. This cut the mean lifespan of the flies by over 70 percent compared to wild-type flies in the same toxic atmosphere. Significantly, overexpression of a sniffer construct not only rescued the mutants from hyperoxia, but actually increased their lifespan beyond that of normal flies. The hyperoxia also caused neurodegeneration as visualized histologically. This was accompanied by substantial apoptosis within the entire brain. As with lifespan, overexpression of sniffer protected the flies against neurodegeneration. Overall, the data suggests that carbonyl reductases could play a role in protecting neurons against oxidative damage.

Other genes that may protect against oxidative damage include superoxide dismutases, which have also been shown to increase lifespan in worms and flies. To characterize the relationship between aging and oxidative stress, John Tower and colleagues from UCLA compared gene expression profiles of aging and oxygen-stressed flies. Their report appears in this week’s PNAS online. First author Gary Landis and colleagues profiled over 13,000 Drosophila genes in young, old, and 100 percent oxygenated insects. They found that aging and oxidative stress lead to induction of a similar set of genes, including those for purine biosynthesis, heat shock, antioxidant, and immune response. Similar experiments comparing aging animals have been carried out previously (see ARF related news story).—Tom Fagan