October 31, 2013
Folks, yeast has been on a roll lately with regard to helping to understand and finding treatments for human disease. Last week we talked about how synthetic lethal screens may find new, previously unrecognized druggable targets for cancer. And this week it is Parkinson’s disease.
Now of course yeast can’t get the traditional sort of Parkinson’s disease …it doesn’t have a brain. But it shares enough biology with us that when it expresses a mutant version of α-synuclein (α-syn) that is known to greatly increase a person’s risk for developing Parkinson’s disease, the yeast cell shows many of the same phenotypes as a diseased neuron. The yeast acts as a stand-in for the neuron.
In a new study out in Science, Tardiff and coworkers use this yeast model to identify a heretofore unknown target for Parkinson’s disease in a sort of reverse engineering process. They screened around 190,000 compounds and looked for those that rescued toxicity in this yeast model. They found one significant hit, an N-aryl-benzimidazole (NAB) compound. Working backwards from this hit they identified its target as Rsp5p, a Nedd4 E3 ubiquitin ligase.
The authors then went on to confirm this finding in C. elegans and rat neuron models where this compound halted and even managed to reverse neuronal damage. And for the coup de grace, Chung and coworkers showed in a companion paper that the compound worked in human neurons too. But not just any human neurons.
The authors used two sets of neurons derived from induced pluripotent cells from a single patient. One set of neurons had a mutation in the α-syn gene which is known to put patients at a high risk of Parkinson’s disease-induced dementia. The other set had the mutation corrected. The compound they identified in yeast reversed some of the effects in the neurons with the α-syn mutation without significantly affecting the corrected neurons. Wow.
What makes this even more exciting is that many people thought you couldn’t target α-syn with a small molecule. But as the studies here show, you can target an E3 ubiquitin ligase that can overcome the effects of mutant α-syn. It took an unbiased screen in yeast to reveal a target that would have taken much, much longer to find in human cells.
The mutant α-syn protein ends up in inclusion bodies that disrupt endosomal traffic in the cell. The NAB compound that the authors discovered restored endosomal transport and greatly decreased the numbers of these inclusion bodies. Juicing up Rsp5 seemed to clear out the mutant protein.
The next steps are those usually associated with finding a lead compound—chemical modification to make it safer and more effective, testing in clinical trial and then, if everything goes well, helping patients with Parkinson’s disease. And that may not be all.
The α-syn protein isn’t just involved in Parkinson’s disease. The dementia associated with this protein is part of a larger group of disorders called dementia with Lewy bodies that affects around 1.3 million people in the US. If everything goes according to plan, many of these patients may one day thank yeast for their treatment.
by D. Barry Starr, Ph.D., Director of Outreach Activities, Stanford Genetics