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UPenn-Led Yeast Tox Study Builds on Commercial Parkinson's Model Developed at Whitehead

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A team led by scientists from the University of Pennsylvania School of Medicine has identified a potential link between genetic and environmental causes of Parkinson's disease in a yeast cell model, UPenn said this week.

The findings appear to validate a similar yeast-based drug-discovery model previously developed in part by one of the UPenn scientists, Aaron Gitler, while he was a postdoc at the Whitehead Institute for Biomedical Research.

That technology has since been licensed by Whitehead to FoldRx, a Cambridge, Mass.-based company developing drugs to treat protein misfolding diseases such as Parkinson's.

UPenn’s research, published online this week in Nature Genetics, was co-authored by Gitler and UPenn colleague Alessandra Chesi with contributions by researchers from Whitehead, Purdue University, and the University of Alabama.

In the paper, the researchers show how they identified a genetic interaction in yeast cells between two Parkinson's disease genes, α-synuclein and YPK9, a yeast analog of the human gene PARK9. Specifically, they determined that the YPK9 protein can protect cells from manganese poisoning, which in humans resembles Parkinson's disease.

While this discovery on its own has implications for understanding manganese poisoning, which is prevalent in occupations such as mining, welding, and steel working, it also has an important link to previous work conducted by Gitler as a postdoc in the Whitehead lab of FoldRx co-founder Susan Lindquist.

At the time, the Lindquist lab studied Parkinson's disease by developing a yeast model that expressed α-synuclein, a protein normally found in human brain tissue that misfolds to form clumps, a process that is highly implicated in the onset of Parkinson's.

According to Gitler, just as YPK9 protects yeast cells from manganese poisoning, it protects the yeast cell model from the detrimental effects of α-synuclein misfolding. Gitler, Lindquist, and others also showed that the YPK9 human analog PARK9 protects neurons from the toxic effects of misfolded α-synuclein.

FoldRx has licensed the yeast cell screening model and associated genes from Whitehead, and is using the model to develop potential neuroprotective drugs for Parkinson's.

Therefore, UPenn’s recent findings linking manganese poisoning with the α-synuclein disease pathway may help validate that model.

"Basically, Whitehead has licensed to FoldRx results of our genetic screen looking for genetic modifiers of alpha-synuclein toxicity," Gitler, now an assistant professor of cell and developmental biology at UPenn, told BTW this week. "The PARK9 gene … was one of the genes that FoldRx licensed, and it turns out that it is able to rescue alpha-synuclein toxicity. We subsequently figured out that one of the functions of the yeast version of this gene is to protect against manganese toxicity."

Gitler added that his group identified "about 70 or 75 yeast genes that can protect against alpha-synuclein toxicity. It turns out in this paper that one of those genes on our list — this YPK9 gene — is a true Parkinson's gene.

"What that means is that maybe some of these other genes that we found might also turn out to play an important role in the disease," he said. "So I think this paper makes those other genes even more interesting, and maybe validates the whole approach."

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FoldRx CEO Richard Labaudinière echoed Gitler's comments. "When you think about Parkinson's, you don't typically think about yeast," Labaudinière said. "But if you express this alpha-synuclein protein in yeast, then you can recapitulate the toxic phenotype. It's really what people think is happening in Parkinson's."

In the case of the most recent paper, "a gene that has shown to be protective in human cells has also been shown to be protective in yeast," Labaudinière said. "We see this as a validation of the model for drug discovery in Parkinson's."

Labaudinière declined to elaborate on the details of FoldRx's licensing deal with Whitehead, saying only that the company has licensed several patents and patent applications covering the yeast platform that overexpresses α-synuclein, as well as all the genes involved.

Gitler confirmed that as a co-inventor on at least some of the Whitehead work that FoldRx licensed, he would likely be eligible to receive royalties if the company is able to market a Parkinson's therapy based on those discoveries.

And even though manganese poisoning and Parkinson's disease share a similar genetic pathway, Labaudinière said that FoldRx is currently not interested in the most recent discoveries by Gitler and colleagues, However, the company may continue to work with Gitler to explore the use of yeast models for other diseases caused by protein misfolding.

"Yeast is not only a good model for Parkinson's, but for many diseases," Labaudinière said. "There is a protein called GDP43 that has been linked to [amyotrophic lateral sclerosis], and Aaron has been able to show that when you overexpress this in yeast you have aggregation and toxicity. It's something we are now looking at."

Indeed, as reported last April by BTW sister publication Cell-Based Assay News, Gitler and colleagues published a paper in the Proceedings of the National Academy of Sciences describing the yeast-based genetic screening model for ALS.

Labaudinière said FoldRx may want to work with Gitler's lab at UPenn to further explore what genes are implicated in modulating GDP43 toxicity in ALS. He declined to elaborate.

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