Novel drug discovery tool could identify promising new therapies for Parkinson's disease

July 13, 2009

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.

Joshua Kritzer, Ph.D., a chemist and postdoctoral fellow in Dr. Lindquist's lab, designed and executed the cyclic peptide strategy. His procedure involves exposing yeast cells to short snippets of DNA that the cells can absorb and use to make cyclic peptides. Then, he flips the genetic switch that causes the cells to produce toxic levels of alpha-synuclein. If the yeast make cyclic peptides that suppress alpha-synuclein toxicity, they live; if not, they die. This simple assay enables testing millions of cyclic peptides simultaneously in millions of yeast cells. The process is extremely rapid and much less expensive compared to other techniques used to screen large number of chemicals with an eye toward new drugs.

"We are making the yeast do a ton of work for us. They make the compounds and then they tell us which ones are functional," Dr. Kritzer says. Out of a library of 50 million cyclic peptides, only two saved the yeast from alpha-synuclein toxicity.

Dr. Lindquist's team collaborated with other researchers to test these two cyclic peptides in C. elegans, a millimeter-long worm with a small number of dopamine-producing neurons that are easy to examine and count. Those neurons are vulnerable to alpha-synuclein toxicity, but they were less vulnerable and more likely to survive in worms that were genetically modified to make either of the two cyclic peptides. Guy Caldwell, Ph.D., and Kim Caldwell, Ph.D., professors of biology at the University of Alabama in Tuscaloosa developed this C. elegans model, and performed the testing.

The researchers have not yet determined why the cyclic peptides are protective. They found that the cyclic peptides do not affect a system of transport inside cells known as vesicle trafficking - which was a surprise, since alpha-synuclein and other proteins that have been implicated in human Parkinson's disease are believed to play a role in vesicle trafficking. However, the researchers observed that the two peptides share a structure that may hold clues to their targets.

"This protein structure has important biological functions," says Dr. Kritzer. It is found in a class of antioxidant proteins known as thioredoxins, in proteins that shuttle metals around a cell, and in proteins that regulate gene activity. The connection to antioxidants and to metals ties into other lines of research. NINDS is currently supporting clinical trials in patients to test whether specific antioxidants slow the progression of Parkinson's disease. High doses of heavy metals such as lead, manganese, iron and mercury are known to be toxic to brain cells.

The researchers are conducting further experiments to explore how cyclic peptides prevent cell death. They are also adapting their system for making cyclic peptides so that it can be used in other cell types (including human cells) and other diseases.
-end-
NINDS (www.ninds.nih.gov) is the nation's primary supporter of biomedical research on the brain and nervous system.

The National Institutes of Health (NIH) -- The Nation's Medical Research Agency -- includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Reference: Kritzer JA et al. "Rapid Selection of Cyclic Peptides that Reduce alpha-Synuclein Toxicity in Yeast and Animal Models." Nature Chemical Biology, published online July 13, 2009.

For more information about Parkinson's disease, visit http://www.ninds.nih.gov/disorders/parkinsons_disease/parkinsons_disease.htm

NIH/National Institute of Neurological Disorders and Stroke

Related Neurons Articles from Brightsurf:

Paying attention to the neurons behind our alertness
The neurons of layer 6 - the deepest layer of the cortex - were examined by researchers from the Okinawa Institute of Science and Technology Graduate University to uncover how they react to sensory stimulation in different behavioral states.

Trying to listen to the signal from neurons
Toyohashi University of Technology has developed a coaxial cable-inspired needle-electrode.

A mechanical way to stimulate neurons
Magnetic nanodiscs can be activated by an external magnetic field, providing a research tool for studying neural responses.

Extraordinary regeneration of neurons in zebrafish
Biologists from the University of Bayreuth have discovered a uniquely rapid form of regeneration in injured neurons and their function in the central nervous system of zebrafish.

Dopamine neurons mull over your options
Researchers at the University of Tsukuba have found that dopamine neurons in the brain can represent the decision-making process when making economic choices.

Neurons thrive even when malnourished
When animal, insect or human embryos grow in a malnourished environment, their developing nervous systems get first pick of any available nutrients so that new neurons can be made.

The first 3D map of the heart's neurons
An interdisciplinary research team establishes a new technological pipeline to build a 3D map of the neurons in the heart, revealing foundational insight into their role in heart attacks and other cardiac conditions.

Mapping the neurons of the rat heart in 3D
A team of researchers has developed a virtual 3D heart, digitally showcasing the heart's unique network of neurons for the first time.

How to put neurons into cages
Football-shaped microscale cages have been created using special laser technologies.

A molecule that directs neurons
A research team coordinated by the University of Trento studied a mass of brain cells, the habenula, linked to disorders like autism, schizophrenia and depression.

Read More: Neurons News and Neurons Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.