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Calculating gene and protein connections in a Parkinson's disease model

5,500 yeast strains (Saccharomyces cerevisiae). These strains are based on a yeast model that creates large amounts of the protein alpha-synuclein, thereby mimicking the toxic effects of alpha-synuclein accumulation in Parkinson's disease patients' brain cells.

Ernest Fraenkel, Assistant Professor of Biological Engineering at MIT, says that the alpha-synuclein data are an excellent test case for the algorithm, which has lead to new insights from existing data.

"The connection between alpha-synuclein and Parkinson's disease is enigmatic," says Fraenkel. "We have wonderful data from the yeast model, but despite this richness of data, so little is known about what alpha-synuclein really does in the cell."

Using these data, ResponseNet identified several links between alpha-synuclein toxicity and basic cell processes, including those used to recycle proteins and to usher the cell through its normal life cycle.

Surprisingly, ResponseNet also tied alpha-synuclein toxicity to a highly-conserved pathway targeted by cholesterol-lowering statin drugs and another pathway targeted by the immunosuppressing drug rapamycin.

To confirm ResponseNet's links and to test how these two pathways could affect alpha-synuclein toxicity, researchers 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, the yeast reduced their growth rate, an indicator that the yeast had gotten sicker. However, when researchers added the molecule ubiquinone (also known as coenzyme Q10 or CoQ10), which is farther downstream in the statin network and possibly undersynthesized in alpha-synuclein-containing yeast, ubiquinone modestly suppressed alpha-synuclein toxicity.

All of these results validated the hypotheses based on ResponseNet's network.

"ResponseNet provides a wealth of new informa

Contact: Nicole Giese
Whitehead Institute for Biomedical Research

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