Yeast model yields insights into Parkinson’s disease

Scientists who developed the first yeast model of Parkinson’s disease (PD) have been able to describe the mechanisms of an important gene’s role in the disease. Tiago Fleming Outeiro, Ph.D., and Susan Lindquist, Ph.D., of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, studied the gene’s actions under normal conditions and under abnormal conditions to learn how and when the gene’s product, alpha-synuclein, becomes harmful to surrounding cells. The scientists created a yeast model that expresses the alpha-synuclein gene, which has been implicated in Parkinson’s disease (PD). Yeast models are often used in the study of genetic diseases because they offer researchers a simple system that allows them to clarify how genes work.

The National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, funded the study, which appears in the December 5, 2003, issue of Science.

The alpha-synuclein protein, which is found broadly in the brain, has been implicated in several neurodegenerative disorders. Sometimes a mutation or a misfolding of the protein causes the problems; other times there are too many copies of the normal gene. A study earlier this year reported that patients with a rare familial form of PD had too many normal copies of the alpha-synuclein gene, which resulted in a buildup of protein inside brain cells, causing the symptoms of PD.

Drs. Outeiro and Lindquist conducted their study by creating one yeast that expresses wild type synuclein, using the normal gene, and another yeast that expresses two mutant forms, using a mutated version of the gene found in patients with PD.

One theory for the cause of PD is that an aging brain no longer has the capacity to cope with accumulating or misfolding proteins. A normal healthy brain has the ability to clear out excess or mutant proteins through a process known as the quality control system. In the yeast model of PD, when the scientists doubled the expression of the alpha-synuclein gene it “profoundly changed” the fate of the yeast’s quality control system, and alpha-synuclein appeared in large clumps of cells (inclusion bodies). This did not happen when they studied the actions of a single copy of the wild type synuclein. These inclusion bodies have a toxic effect that causes cell death and neurodegeneration.

“Just a twofold difference in expression was sufficient to cause a catastrophic change in behavior,” the scientists report in their paper.

“These changes may give insight into important changes that happen when alpha-synuclein is overexpressed in Parkinson’s patients,” said Diane Murphy, Ph.D., a program director at the NINDS. “Dr. Lindquist is well known for her studies of yeast models of prion disease, and we are delighted she has extended her research to the important field of Parkinson’s disease.”

PD is the second most common neurodegenerative disease after Alzheimer’s disease and is thought to affect 500,000 Americans.

The NIH’s National Institute of Neurological Disorders and Stroke leads Federal efforts to conduct and support basic and clinical research on diseases of the brain and central nervous system. The agencies are part of the U.S. Department of Health and Human Services.

“Yeast Cells Provide Insight into Alpha-Synuclein Biology and Pathobiology,” Outeiro, T.F. and Lindquist, S. Science, Vol. 302, pp. 1772-1775.