New & Noteworthy
September 5, 2013
Huntington’s disease (HD) is a truly awful, inherited and ultimately fatal genetic disease. People with this neurodegenerative disorder typically start having trouble with their coordination and displaying mild cognitive and psychiatric problems in mid-adulthood. Their symptoms continue to worsen, with most of these folks passing away within 20 years of their diagnosis. This disease strikes down adults in their prime.
Scientists have known for decades what causes HD—too many CAG repeats in the huntingtin (htt) gene. What they haven’t been able to figure out is what to do about this misfolded protein. To date, the treatment options are very limited.
A new study out by Mason and coworkers has a chance to change all of that. Using an unbiased screen in Saccharomyces cerevisiae, these authors were able to identify a class of proteins, the glutathione peroxidases, that when overexpressed protected yeast from the harmful effects of the mutant htt protein. They then followed up and showed that these proteins had a similar effect in fruit fly and mouse HD cell models as well as in a whole fruit fly model. And this isn’t even the exciting part.
There are druggable small molecules that when added to cells (or whole animals) can upregulate the activity of glutathione peroxidases. The authors used one of these molecules, ebselen, and showed that it mimicked the effects of overexpressing various glutathione peroxidases in cells and, more importantly, in whole fruit flies. When these flies were fed ebselen, their neurons degenerated at a much slower rate. Mason and coworkers have identified a small molecule that can mitigate the effects of the mutant htt protein in model systems.
While we shouldn’t get ahead of ourselves here, this is all pretty exciting news. How cool would it be if one day people with HD lived longer, happier lives because of a drug identified using our favorite model organism? (Pay attention NIH!)
Mason and coworkers looked in S. cerevisiae for open reading frames that, when overexpressed, would lower the toxicity of the mutant htt protein. They identified 317 of these, and used a variety of bioinformatics tools to group them into different pathways and gene networks.
In the end, they decided to focus on two powerful suppressors, the glutathione peroxidases Gpx1p and Hyr1p (also known as Gpx3p), for a variety of different reasons. These proteins are powerful antioxidants, and oxidative stress is known to contribute to HD symptoms. Also, these proteins aren’t already upregulated in patients with Huntington’s disease, suggesting that it might be possible to increase their activity using drug therapy.
Now of course yeast aren’t mammals, so Mason and coworkers needed to show that having extra glutathione peroxidase activity would help in mammalian cells too. And this is just what they did: adding a mouse version of glutathione peroxidase, mGPx1, suppressed cellular toxicity in mouse cells that overexpressed the mutant form of htt.
Next they tested whether activating glutathione peroxidases would have the same effect. They focused specifically on a selenocysteine-containing molecule called ebselen because it is highly bioavailable, can cross the blood-brain barrier (critical for HD) and has been used in treating stroke and noise induced hearing loss. When added to the mouse HD model cell system, ebselen had very similar effects to overexpressing mGPx1.
So upregulating glutathione peroxidase activity by either overexpressing mGPx1 or adding the small molecule ebselen appears to help in a couple of different model cell systems. But what about a whole animal? Looks like it can help there too.
Mason and coworkers looked at HD in a fruit fly. When they added mGPx1 to this model fly, various neurons in these flies were protected from the effects of HD. And they got similar results when they fed these flies the molecule ebselen.
As a final experiment, the authors wanted to figure out whether glutathione peroxidases were really having their effect because of their antioxidant activity. In one way it makes sense that this activity is why they are so effective at mitigating the effects of the mutant HD—scientists have known for a while that oxidative stress is a major contributor to symptoms of HD. But on the other hand no antioxidant therapies have worked to date for HD. In fact, if anything they made matters worse. So one thought was that there was something special about the antioxidant activity of these proteins. For these experiments, they needed to go back to yeast.
The authors looked at a variety of antioxidant proteins, including superoxide dismutase, catalases, and glutathione reductases, and none protected the yeast from the effects of the mutant htt protein. They then checked the effects of catalase and superoxide dismutase in the HD mouse cells, and again saw no effect.
It is well known that antioxidants negatively affect autophagy and that disrupting this process can make HD symptoms worse. From this the authors reasoned that glutathione peroxidases were special because they were antioxidants that did not affect autophagy. They provided support for their idea by showing that ebselen did not affect autophagy in yeast while a control antioxidant, N-acetylcysteine, did.
Once again, yeast shows why it is such an important tool in finding potential new treatments for human disease. Without the unbiased screen, it’s difficult to imagine how scientists would have found this target. You can really only do this easily in a beast like yeast.
Symptoms like these may one day be delayed because of the awesome power of yeast genetics.
by D. Barry Starr, Ph.D., Director of Outreach Activities, Stanford Genetics