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Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity

Nature Genetics volume 41, pages 316–323 (2009)Cite this article

Abstract

Cells respond to stimuli by changes in various processes, including signaling pathways and gene expression. Efforts to identify components of these responses increasingly depend on mRNA profiling and genetic library screens. By comparing the results of these two assays across various stimuli, we found that genetic screens tend to identify response regulators, whereas mRNA profiling frequently detects metabolic responses. We developed an integrative approach that bridges the gap between these data using known molecular interactions, thus highlighting major response pathways. We used this approach to reveal cellular pathways responding to the toxicity of alpha-synuclein, a protein implicated in several neurodegenerative disorders including Parkinson's disease. For this we screened an established yeast model to identify genes that when overexpressed alter alpha-synuclein toxicity. Bridging these data and data from mRNA profiling provided functional explanations for many of these genes and identified previously unknown relations between alpha-synuclein toxicity and basic cellular pathways.

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Figure 1: Regulatory relationships between genetic and transcriptional data.
Figure 2: Interactome subnetworks connecting genetic and transcriptional data.
Figure 3: Nitrosative stress response to α-syn expression in yeast.
Figure 4: Overexpression of Gip2 causes induced expression of Hsf1 targets.
Figure 5: Effects of the small molecules lovastatin and rapamycin on α-syn toxicity.

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Acknowledgements

E.Y.-L. has been supported by an EMBO long-term postdoctoral fellowship and by a research grant from the National Parkinson Foundation. L.R. has been supported by Roberto Rocca doctoral fellowship and the CSBi Merck-MIT postdoctoral fellowship. L.J.S. was supported by an American Cancer Society postdoctoral fellowship. A.D.G. was a Lilly Fellow of the Life Sciences Research Foundation. M.L.G is supported by a research grant from the National Parkinson Foundation. S.L. is a founder of and has received consulting fees from FoldRx Pharmaceuticals, a company that investigates drugs to treat protein folding diseases. A.D.G., A.G.C. and S.L. are inventors on patents and patent applications that have been licensed to FoldRx. E.F. is the recipient of the Eugene Bell Career Development Chair. This work was supported in part by HHMI and by MGH/MIT Morris Udall Center of Excellence in PD Research NS38372. We thank M. Taipale, S. Treusch and G. Caraveo Piso for helpful discussions and comments and T. DiCesare for help with figures. L.R. thanks G. Casari and S. Cerutti for support and helpful discussions.

Author information

Author notes

  1. Aaron D Gitler, Anil G Cashikar & Oliver D King

    Present address: Present addresses: Department of Cell and Developmental Biology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA (A.D.G.), Medical College of Georgia, Augusta, Georgia, USA (A.G.C.) and Boston Biomedical Research Institute, Watertown, Massachusetts, USA (O.D.K.).,

  2. Esti Yeger-Lotem and Laura Riva: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Esti Yeger-Lotem, Laura Riva & Ernest Fraenkel

  2. Whitehead Institute for Biomedical Research, Cambridge, 02142, Massachusetts, USA

    Esti Yeger-Lotem, Linhui Julie Su, Aaron D Gitler, Anil G Cashikar, Oliver D King, Pavan K Auluck, Melissa L Geddie, Julie S Valastyan & Susan Lindquist

  3. Departments of Pathology and Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Pavan K Auluck

  4. Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Julie S Valastyan

  5. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    David R Karger & Ernest Fraenkel

  6. Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Susan Lindquist

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Correspondence to Susan Lindquist or Ernest Fraenkel.

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Competing interests

S.L. is a founder of, a former member of the Board of Directors, and has received consulting fees from FoldRx Pharmaceuticals, a company that investigates drugs to treat protein-folding diseases. A.D.G. and S.L. are inventors on patents and patent applications that have been licensed to FoldRx. S.L. is also a member of the Board of Directors of Johnson & Johnson.

E.Y.-L., L.R., D.K. and E.F. have filed a patent application for the ResponseNet algorithm.

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Yeger-Lotem, E., Riva, L., Su, L. et al. Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity. Nat Genet 41, 316–323 (2009). https://doi.org/10.1038/ng.337

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