Researchers funded by the National Institutes of Health have turned simple baker’s yeast into a virtual army of medicinal chemists capable of rapidly searching for drugs to treat Parkinson's disease.
In a study published online today in Nature Chemical Biology, the researchers showed that they can rescue yeast cells from toxic levels of a protein implicated in Parkinson's disease by stimulating the cells to make very small proteins called cyclic peptides. Two of the cyclic peptides had a protective effect on the yeast cells and on neurons in an animal model of Parkinson's disease.
"This biological approach to compound development opens up an entirely new direction for drug discovery, not only for Parkinson's disease, but theoretically for any disease where key aspects of the pathology can be reproduced in yeast," says Margaret Sutherland, Ph.D., a program director at NIH's National Institute of Neurological Disorders and Stroke (NINDS). "A key step for the future will be to identify the cellular pathways that are affected by these cyclic peptides."
The research emerged from the lab of Susan Lindquist, Ph.D., a professor of biology at the Massachusetts Institute of Technology (MIT), a member of the Whitehead Institute for Biomedical Research, and a Howard Hughes Medical Institute investigator. Dr. Lindquist is also an investigator at the Massachusetts General Hospital (MGH)/MIT Morris K. Udall Center for Excellence in Parkinson's Research, one of 14 such centers funded by NINDS to develop treatment breakthroughs for Parkinson's disease. The study received additional funding from NIH's National Institute of Environmental Health Sciences, and from the Michael J. Fox Foundation and the American Parkinson's Disease Association.
Parkinson's disease attacks cells in a part of the brain responsible for motor control and coordination. As those neurons degenerate, the disease leads to progressive deterioration of motor function including involuntary shaking, slowed movement, stiffened muscles, and impaired balance. The neurons normally produce a chemical called dopamine. A synthetic precursor of dopamine called L-DOPA or drugs that mimic dopamine's action can provide symptomatic relief from Parkinson's disease. Unfortunately, these drugs lose much of their effectiveness in later stages of the disease, and there is currently no means to slow the disease's progressive course.
In most cases, the cause of Parkinson's disease is unknown, but there are recent, tantalizing clues. Investigators have discovered that vulnerable brain cells in patients with Parkinson's disease accumulate a protein called alpha-synuclein. Moreover, genetic abnormalities in alpha-synuclein cause a rare familial form of the disease. Dr. Lindquist and her team previously showed that when yeast cells are engineered to produce large amounts of human alpha-synuclein, they die.
In their new study, Dr. Lindquist and her team tested whether yeast could make cyclic peptides that would save them from alpha-synuclein's toxicity. Cyclic peptides are fragments of protein that connect end-to-end to form a circle. Although cyclic peptides are synthetic, they resemble structures that are found in natural proteins and protein-based drugs, including pain killers, antibiotics and immunosuppressants. Cyclic peptides that suppress alpha-synuclein toxicity could be candidate drugs for Parkinson's disease, or they could help researchers identify new drug targets for the disease.
"Our technique, which capitalizes on a long line of investigation in my lab, will lead to a whole new way to obtain small molecule tools useful for improving our understanding of disease mechanisms and for developing new therapies," says Dr. Lindquist. She notes that her lab and others have modeled many human diseases in yeast and in other kinds of cells.