Methods of identifying agents that mediate polypeptide aggregation
The present invention is based, in part, on the discovery of methods for identifying compounds that mediate (by promoting or inhibiting) protein-protein interaction (e.g., aggregation, dimerization, or other physiologically significant association). Compounds that mediate such interaction, which are also within the scope of the invention, can be used to treat Alzheimer's disease, disorders associated with expanded CAG repeats (such as Huntington's disease), and disorders in which polyglutamine-containing transcription factors or coactivators are undesirably active (e.g., disorders associated with homodimerization of jun or hexamerization of p53.
1. A method for identifying a compound that inhibits the aggregation of glutamine-rich polypeptides, the method comprising:
obtaining a cell that expresses a fusion protein comprising a glutamine-rich polypeptide and a fluorescent polypeptide;
exposing the cell to the compound;
measuring the fluorescence emitted by the cell for a first time;
incubating the cell with the compound; and
measuring the fluorescence emitted by the cell for a second time, wherein an increase in the fluorescence emitted by the cell the second time, relative to the first time, indicates that the compound inhibits the aggregation of glutamine-rich polypeptides.