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Yeast Helps Researchers Better Understand Parkinson's Mystery Public release date: 4-Dec-2003 Contact: Kelli Whitlock or David Cameron [log in to unmask] 617-258-5183 Whitehead Institute for Biomedical Research Yeast helps researchers better understand Parkinson's mystery 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." ### SOURCE: EurekAlert, DC http://www.eurekalert.org/pub_releases/2003-12/wifb-yhr120303.php * * * NewNeural CSO Receives Grant from Alzheimers Association; Study to Investigate Link Between Alzheimer's Disease Protein and Stem Cell Biology December 04, 2003 11:55 AM US Eastern Timezone CHICAGO--(BUSINESS WIRE)--Dec. 4, 2003--NewNeural LLC, (NewNeural) an emerging biotechnology company that is developing adult stem cell therapy products, today announced that Kiminobu Sugaya, PhD., NewNeural's founder, chairman, and chief science officer, has been awarded a $240,000 grant from the Alzheimer's Association. The grant was awarded to Sugaya through the University of Illinois at Chicago and will be used to further study the role of a protein in the migration and differentiation of stem cells in the brain. Sugaya, who is also an associate professor of psychiatry at the University of Illinois at Chicago, conducted preliminary studies which demonstrated that beta-amyloid precursor protein (APP) affects the migration and differentiation pattern of stem cells in the brain. This protein, which produces amyloid plaques in the brain of Alzheimer's patients, may play a key role in the degenerative disease, through its controlling effect on the brain's stem cells. Sugaya hopes these studies, which are the basis for one of his patent applications, will ultimately lead to the development of a novel therapeutic approach for battling Alzheimer's disease. "The objective of our research is to clearly understand the functions of APP in neuro-stem cell biology," said Sugaya. "We believe that the metabolism of this protein may play an important role in Alzheimer's disease. If we can identify and isolate the specific role this protein plays in differentiating neuro-stem cells, we can then incorporate these findings in our strategy for neural replacement therapy, the foundation of our product pipeline." Sugaya will collaborate with the Karolinska Institute in Sweden and the University of Heidelberg in Germany for his work in this field. Earlier this year, Sugaya received a $1.4 million grant from the National Institute of Health (NIH) for his work on neural replacement strategies using stem cells produced from adult human bone marrow. Sugaya has successfully demonstrated in vitro and in multiple animal transplantation studies that cells produced from human bone marrow using his technology can differentiate into neurons. About NewNeural NewNeural LLC. (NewNeural) is an emerging biotechnology company in the pre-clinical stage that intends to develop products based on adult stem cells to treat diseases of and injuries to the central nervous system such as stroke, ALS, Parkinson's and spinal cord injury. NewNeural believes it has a unique, protected, technology platform which includes a small molecule and a cell therapy approach that uses a patient's own easily accessible cells (bone marrow) to replace damaged brain cells without the need for immune suppression and without using embryonic or fetal tissue. For more information about NewNeural and its programs visit www.newneural.com. About The Alzheimer's Association The Alzheimer's Association is the world leader in Alzheimer research and support. Having awarded more than $150 million to nearly 1,300 projects, the Alzheimer's Association is the largest private funder of Alzheimer research. The association's vision is a world without Alzheimer's disease. For more information about Alzheimer's disease, research and treatments, please call 800-272-3900. Contacts: NewNeural Bob Gonzalez, 630-428-4634 [log in to unmask] or The ChemPetitive Group Murad Sabzali, 630-400-3042 [log in to unmask] SOURCE: Business Wire (press release) http://tinyurl.com/xtkf * * * ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn