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Novel drug discovery tool could identify promising new therapies for Parkinson's disease
Date:7/13/2009

n 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
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Contact: Daniel Stimson
stimsond@ninds.nih.gov
301-496-5751
NIH/National Institute of Neurological Disorders and Stroke
Source:Eurekalert

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