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UPenn Yeast Model Mimics Proteinopathy In Certain Neurodegenerative Diseases

This article has been updated from a previous version to correct the name of one of the journals that published studies on the role of TDP-43 mutations in ALS.
Scientists at the University of Pennsylvania this week announced that they have developed a yeast model that can screen for drugs that treat neurodegenerative diseases including amyotrophic lateral sclerosis. 
The researchers’ work centered on TDP-43, a ubiquitously expressed nuclear protein that undergoes a pathological conversion to aggregated cytoplasmic localization in regions of the nervous system affected by ALS and frontotemporal dementia with ubiquitin-positive inclusions.
Indeed, over the last month or so four papers have identified mutations in the TDP-43 in patients with ALS. The articles appeared in the May issue of Lancet Neurology, online on March 30 in Nature Genetics, in the March 21 issue of Science, and online on February 20 in the Annals of Neurology.


“This is very exciting, because it proves that TDP-43 is a direct cause of the disease,” Aaron Gitler, an assistant professor of cell and developmental biology at the UPenn School of Medicine, told CBA News this week.
The study, which appears online this week in the Proceedings of the National Academy of Sciences, resulted in an “engineered system controlled by a galactose-regulated promoter that we can use to induce expression of TDP-43 in yeast cells,” said Gitler.
He added that his lab can use these cells to screen hundreds of thousands of small molecules “to see if we can identify a compound that can reverse the effects of TDP-43,” or screen for genes with the same effect.
“We also want to see if we can take what we learned from our yeast model and take it into animal models for validation,” said Gitler.
Gitler, who was also a corresponding author on the paper, said that yeast cells are easy to handle and divide quickly.
“The protein-aggregation process in humans takes decades or at least many years to happen,” he said. “This process can be visualized in yeast cells in a matter of hours.”
Fluorescent proteins can be attached to TDP-43 so that aggregate formation can be visualized, Gitler said. “We put human TDP-43 into yeast cells, and when it was expressed at low levels, it behaved much like it does in human cells,” he said. “It goes to the cell nucleus and the cells tolerated this.”
When TDP-43 was overexpressed, it changed its localization and started to form aggregates in the yeast cells, and was sequestered outside of the nucleus in a manner reminiscent of human neurons that have TDP-43 aggregates, said Gitler.

“Lately I have seen an increase in the use of yeast as a test tube to investigate the biology of disease genes found in the human.”

“This was exciting because it meant that we could mimic some aspects of the human disease in our yeast model,” he explained.  
When the researchers expressed TDP-43 in yeast cells and observed it aggregating, the aggregates were very toxic to the cells, Gitler said, adding that the finding “was the first demonstration” of such a phenomenon.
This toxicity may explain the pathology of diseases such as ALS or FTD, said Gitler.
Gitler said his next step “is to actually do the screens to find the drugs or the genes that can reverse the toxic effects of TDP-43 aggregation.” He said that this work is currently ongoing.
With his and other work serving as evidence that mutations in TDP-43 are linked to ALS and other neurodegenerative disease, Gitler said he believes his model will benefit researchers studying the consequences of those mutations.
“We have now been putting those patient-linked mutations of TDP-43 back into yeast and testing the effects,” said Gitler.  “This year we hope to complete small-molecule and genetic screens.”
He also said that his lab is interested in pursuing collaborations with academia as well as industry. “We are not a drug-discovery lab, so we are looking to partner with others who have more expertise than us.”
Some agreements are pending, but “I do not know all of the final details,” Gitler said.
Yeast Rising
The use of yeast in drug discovery continues to grow. In the past, the biggest use of the organism was to identify genes that could then be looked for in humans, Tim Galitski, an associate professor at the Institute for Systems Biology in Seattle, told CBA News this week.
Galitski was one of the ISB investigators who developed a method that can predict how combinations of gene mutations affect the way yeast cells respond to environmental stress (see CBA News, 5/4/07).
“Lately I have seen an increase in the use of yeast as a test tube to investigate the biology of disease genes found in the human,” Galitski said. “I think that [the PNAS] paper is a nice example of that.”
One of the key findings reported in the paper is that the same basic phenomenon of TDP-43 protein aggregation is occurring in the yeast system that occurs in the human, said Galitski. In addition, they found that this protein aggregation creates cellular toxicity in the yeast as it does in the human, and that some of the key biological, biochemical, and genetic characteristics are preserved from human to yeast.
The experimental tractability of yeast makes it a good model organism to help understand the protein aggregation process, and to identify compounds or small molecules that would have some effect in the human system, Galitski said.   
One recent example of the growing importance of yeast in drug discovery, Galitski said, was GlaxoSmithKline’s $720 million acquisition last week of Sirtris, a young company that uses yeast cells to study the aging process.
“By studying the genetic and biochemistry of aging processes in yeast, [scientists] have found drugs that would slow the aging processes [in yeast], and have found that the same aging processes are happening in humans,” said Galitski. The same drugs that are efficacious in yeast are also potentially efficacious in mammalian cell systems, and possibly in vivo in humans as well, he said.  
“I think that is also a nice example of the direct relevance of yeast biology to human disease biology.”

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