Rapid selection of cyclic peptides that reduce alpha-synuclein toxicity in yeast and animal models.
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.
Kritzer
Joshua A
JA
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
Hamamichi
Shusei
S
McCaffery
J Michael
JM
Santagata
Sandro
S
Naumann
Todd A
TA
Caldwell
Kim A
KA
Caldwell
Guy A
GA
Lindquist
Susan
S
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000096:biosynthesis* / Q000235:genetics; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D051844:alpha-Synuclein / Q000096:biosynthesis*
D019151:Peptide Library; D010456:Peptides, Cyclic; D051844:alpha-Synuclein