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From Yeast to Humans: Leveraging New Approaches in Yeast to Accelerate Discovery of Therapeutic Targets for Synucleinopathies

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Yeast Systems Biology

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2049))

Abstract

Neurodegenerative diseases (ND) represent a growing, global health crisis, one that lacks any disease-modifying therapeutic strategy. This critical need for new therapies must be met with an exhaustive approach to exploit all tools available. A yeast (Saccharomyces cerevisiae) model of α-synuclein toxicity—the protein causally linked to Parkinson’s disease and other synucleinopathies—offers a powerful approach that takes advantage of the unique offerings of this system: tractable genetics, robust high-throughput screening strategies, unparalleled data repositories, powerful computational tools, and extensive evolutionary conservation of fundamental biological pathways. These attributes have enabled genetic and small molecule screens that have revealed toxic phenotypes and drug targets that translate directly to patient-derived iPSC neurons. Extending these insights, recent advances in genetic network analyses have generated the first “humanized” α-synuclein network, which has identified druggable proteins and led to validation of the toxic phenotypes in patient-derived cells. Unbiased phenotypic small molecule screens can identify compounds targeting critical proteins within α-synuclein networks. While identification of direct drug targets for phenotypic screen hits represents a bottleneck, high-throughput chemical genetic methods provide a means to uncover cellular targets and pathways for large numbers of compounds in parallel. Taken together, the yeast α-synuclein model and associated tools can reveal insights into underlying cellular pathologies, lead molecules and their cognate targets, and strategies to translate mechanisms of toxicity and cytoprotection into complex neuronal systems.

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Acknowledgments

We thank Vikram Khurana for reviewing the manuscript. This chapter was made possible through the innovations and fearless investigations of the late Susan Lindquist (1949–2016). We gratefully dedicate this chapter to her.

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  1. Jeff S. Piotrowski and Daniel F. Tardiff contributed equally.

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  1. Yumanity Therapeutics, Cambridge, MA, USA

    Jeff S. Piotrowski & Daniel F. Tardiff

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  1. Jeff S. Piotrowski
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  2. Daniel F. Tardiff
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Correspondence to Daniel F. Tardiff .

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  1. Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK

    Stephen G. Oliver

  2. Genetadi Biotech, Parque Tecnológico de Bizkaia, Biscay, Spain

    Juan I. Castrillo

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Piotrowski, J.S., Tardiff, D.F. (2019). From Yeast to Humans: Leveraging New Approaches in Yeast to Accelerate Discovery of Therapeutic Targets for Synucleinopathies. In: Oliver, S.G., Castrillo, J.I. (eds) Yeast Systems Biology. Methods in Molecular Biology, vol 2049. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9736-7_24

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  • DOI: https://doi.org/10.1007/978-1-4939-9736-7_24

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