Using a new algorithm called ResponseNet that combines existing data to produce a chart of how cells respond to stimuli, researchers at Whitehead Institute and Massachusetts Institute of Technology have analyzed alpha-synuclein toxicity to identify genes and pathways that can affect cell survival, including those used to recycle proteins and to usher the cell through its normal life cycle.
Because misfolded copies of the alpha-synuclein protein in brain cells are associated with Parkinson’s disease, investigators entered data from screens of 5,500 yeast strains based on a yeast model that creates large amounts of the protein alpha-synuclein. The model mimics the toxic effects of alpha-synuclein accumulation in the brain cells of Parkinson’s disease patients.
The team was surprised that ResponseNet also tied alpha-synuclein toxicity to a highly-conserved pathway targeted by cholesterol-lowering statin drugs and a separate pathway targeted by the immunosuppressing drug rapamycin.
To confirm those links and to test how the two pathways could affect alpha-synuclein toxicity, the scientists added either rapamycin or the statin lovastatin to yeast model cultures. When the researchers added a low dose of rapamycin to the yeast model, the drug was toxic to the yeast. When lovastatin was added, it reduced the yeasts’ growth rate, an indicator that the yeast had gotten sicker. However, when researchers added the molecule ubiquinone—which is farther downstream in the statin network and possibly undersynthesized in alpha-synuclein-containing yeast—the molecule modestly suppressed alpha-synuclein toxicity.
“ResponseNet provides a wealth of new information,” says Susan Lindquist, Ph.D., a Howard Hughes Medical Institute investigator. “Some of the things we have found offer a promise to speed the development of new therapeutic strategies for Parkinson’s disease.”
The article appears in the February 22 online edition of Nature Genetics.
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