CAMBRIDGE, Mass. (Dec. 4, 2003) – Scientists know that in patients with Parkinson's disease, certain proteins in the brain form clusters that somehow contribute to cell death and, eventually, lead to the onset of the disease's debilitating symptoms. The quest to figure out how these clusters form – and how to prevent them – has been slow and difficult.
Now, after years of painstaking research, scientists have succeeded in duplicating the disease's most critical features in the most readily manipulated model organism in existence. In research published in this week's issue of the journal Science, a team from Whitehead Institute for Biomedical Research used common baker's yeast as a living test tube to show how just a small amount of a Parkinson's-related neuronal protein called alpha-synuclein (aSyn) can convince neighboring proteins to abandon their normal shape and form these deadly clusters.
"For the first time we can initiate the process synchronously in living cells and watch what is happening in real time," says Susan Lindquist, director of Whitehead Institute and a lead author of this new study.
A protein's shape is critical to its function: When a protein changes its shape, it changes function, and this can be deadly. Many neurodegenerative diseases such as Parkinson's are thought to be caused by proteins like aSyn that can misfold into abnormal shapes and lose their ability to function correctly or even wreak havoc in the cell.
The Lindquist lab has been studying human proteins in yeast for several years, learning more and more about how proteins misfold and what happens when they do. The similarities in basic cellular processes between humans and yeast were so striking, they decided to see if they could provoke a Parkinson's-like problem in these simple, one-celled fungi.
For the study, Tiago Outeiro (o-TEE-ero), a graduate student in Lindquist's lab and lead author on the paper, assembled a group of yeast cells, each containing varying levels of the aSyn protein.
"Basically, I wanted to see what happens in the cell when we produce just a bit more of this protein than the quality-control system can handle," Outeiro says. "Does the biology of the protein change? Does it simply sit there? Does it cause problems to the cell?"
When aSyn was produced at low levels, it made its way to the cell membrane and appeared to regulate chemical trafficking and metabolism of compounds called lipids – what may be normal functions for this protein. However, when Outeiro studied cells with a slightly higher level of aSyn, he noticed that some of the proteins misfolded and caused others to do the same. The proteins began to form large clusters, and the cell began to die.
What they learned from yeast may have direct application to human disease, Lindquist explains.
"This confirms our suspicion that many of these proteins that cause disease can be very finely balanced, and when you tip the balance over just a little bit, it doesn't take a whole lot (to cause a reaction)," she says. "But the hopeful thing is that it might not take a whole lot to tip the balance back," by devising ways to improve the quality-control mechanisms in cells that normally dispose of misfolded proteins.
Yeast is one of the most thoroughly explored organisms available to scientists, Lindquist notes, adding that the very simplicity of the organism, combined with how much is known about it, is turning other scientists on to the unique value of yeast research.
In a second paper published in the same issue of Science, Lindquist and Outeiro teamed up with Paul Muchowski, an assistant professor in pharmacology at the University of Washington, to explore other uses of Outeiro's yeast model.
The researchers compared aSyn with the protein that causes Huntington's disease, the huntingtin protein (not to be confused with name of the disease), taking advantage of a yeast cell library composed of 4,850 strains in which each cell had a different gene disabled. By placing aSyn and the huntingtin protein into the library separately and then monitoring each cell's reaction, they were able to deduce which genes are important for the cells to survive the toxic insult from aSyn, and which ones are needed to help the cells survive the huntingtin protein.
The results may indicate which genes are important for survival in the Huntington's and Parkinson's disease processes in humans.
"What we found was really surprising," says Muchowski. "Even though both the huntingtin and aSyn protein create almost identical looking clumps in the cells, they're regulated by totally different sets of genes." In order to survive the huntingtin protein, the cells needed genes that were involved with protein folding and quality control. For aSyn, genes involved with lipid metabolism and membrane trafficking kept the cells alive.
"A lot of people had hoped that these two diseases would have common mechanisms and that one drug might cure both of them," says Muchowski. "But now it's fairly clear that researchers might have to look in different directions."
And as scientists seek cures for these and other neurological conditions, the yeast study model developed by Outeiro could be used to test potential therapeutics. Long a staple for studying a variety of diseases – most notably cancer – yeast has been neglected as a test bed for neurological conditions, Lindquist notes. Many researchers assumed the organism was too simple to serve as a good model when studying the complexities of neurodegenerative diseases. But that perception is changing, she adds, and this latest research is contributing to the shift.
In fact, Lindquist suggests, this platform will be an excellent test bed for drug screening, something she plans to explore with corporate partners. Outeiro agrees that yeast will prove to be a powerful medium for testing pharmaceuticals.
"At the basic level, yeast cells are very similar to mammalian cells. So in a sense, yeast is perfect," he notes. Then, with a grin, "In fact, sometimes we need to remind ourselves that yeast isn't a person."
Materials provided by Whitehead Institute For Biomedical Research. Note: Content may be edited for style and length.
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