Document Report Card

ID: ALA1212724

Journal: Nat Chem Biol

Title: Rapid selection of cyclic peptides that reduce alpha-synuclein toxicity in yeast and animal models.

Authors: Kritzer JA, Hamamichi S, McCaffery JM, Santagata S, Naumann TA, Caldwell KA, Caldwell GA, Lindquist S.

Abstract: Phage display has demonstrated the utility of cyclic peptides as general protein ligands but cannot access proteins inside eukaryotic cells. Expanding a new chemical genetics tool, we describe the first expressed library of head-to-tail cyclic peptides in yeast (Saccharomyces cerevisiae). We applied the library to selections in a yeast model of alpha-synuclein toxicity that recapitulates much of the cellular pathology of Parkinson's disease. From a pool of 5 million transformants, we isolated two related cyclic peptide constructs that specifically reduced the toxicity of human alpha-synuclein. These expressed cyclic peptide constructs also prevented dopaminergic neuron loss in an established Caenorhabditis elegans Parkinson's model. This work highlights the speed and efficiency of using libraries of expressed cyclic peptides for forward chemical genetics in cellular models of human disease.

CiteXplore: 19597508

DOI: 10.1038/nchembio.193