MEDICAL: DISEASES: PARKINSON'S DISEASE : MEDICAL: PHARMACY PHARMACEUTICAL PHARMACOLOGY: DRUGS: Novel Drug Discovery Tool Could Identify Promising New Therapies for Parkinson's Disease

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MEDICAL: DISEASES: PARKINSON'S DISEASE : MEDICAL: PHARMACY PHARMACEUTICAL PHARMACOLOGY: DRUGS: Novel Drug Discovery Tool Could Identify Promising New Therapies for Parkinson's Disease

David P. Dillard
Administrator


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MEDICAL: DISEASES: PARKINSON'S DISEASE :
MEDICAL: PHARMACY PHARMACEUTICAL PHARMACOLOGY: DRUGS:
Novel Drug Discovery Tool Could Identify Promising
New Therapies for Parkinson's Disease




Date: Mon, 13 Jul 2009 13:09:53 -0400
From: "NIH OLIB (NIH/OD)" <[hidden email]>
To: [hidden email]
Subject:  Novel Drug Discovery Tool Could Identify Promising
New Therapies for Parkinson's Disease




U.S. Department of Health and Human Services
NATIONAL INSTITUTES OF HEALTH NIH News



National Institute of Neurological Disorders and Stroke (NINDS)
<http://www.ninds.nih.gov/>



Embargoed for Release: Monday, July 13, 2009, 1:00 p.m. EDT




CONTACT:



Daniel Stimson, NINDS

496-5751

e-mail:

[hidden email]



NOVEL DRUG DISCOVERY TOOL COULD IDENTIFY
PROMISING NEW THERAPIES FOR PARKINSON'S DISEASE



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.



NINDS
<http://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


<http://www.nih.gov>




For more information about Parkinson's disease, visit



<http://www.ninds.nih.gov/disorders/ 
parkinsons_disease/parkinsons_disease.htm>



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



<http://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.




##




This NIH News Release is available online at:
<http://www.nih.gov/news/health/jul2009/ninds-13.htm>




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