The research is based on a type of brewer's yeast modified to produce too much of the alpha-synuclein protein in its cells. The resulting cells manifest adverse effects similar to those experienced in brain cells from Parkinson's patients.
Using this yeast strain, the Lindquist team screened 115,000 small compounds to see which ones alleviate the Parkinson's-like traits. During a screen, a compound is added to a small amount of yeast. Researchers can then easily and efficiently detect if that compound changes the yeast's growth rate, compared to a control. The technique takes advantage of the yeast's normally fast growth, which allows researchers to quickly test thousands of compounds, a process that is not possible in other frequently-used Parkinson's disease models.
Four compounds were found to restore the alpha-synuclein yeast cells' growth to 50% of normal yeast cells. Yeast cells that were not treated with the compounds died. The four compounds have similar chemical structures, a finding that indicates they may be acting on the same target or targets. The researchers also identified two commercially available compounds with similar chemical structures and used those in further tests.
To determine if the six compounds would work in animal models of Parkinson's, the scientists tested the compounds in the round worm Caenorhabditis elegans and in rat neurons. In both of these disease models, cells overproduce alpha-synuclein resulting in the same deleterious effects as in the yeast model. During testing, the first four compounds were able to rescue the round worms, while in the rat neurons, three of the four original compounds and one of the commercial compounds improved the nerve cells' growth.
In all of the models, the compounds improved protein trafficking and decreased mitochondrial d
|Contact: Nicole Giese|
Whitehead Institute for Biomedical Research