1. Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity
- Author
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Esti Yeger-Lotem, David R. Karger, Pavan K. Auluck, Oliver D. King, Ernest Fraenkel, Melissa Geddie, Linhui Julie Su, Aaron D. Gitler, Susan Lindquist, Julie S. Valastyan, Laura Riva, and Anil G. Cashikar
- Subjects
Saccharomyces cerevisiae Proteins ,Transcription, Genetic ,Gene regulatory network ,Mevalonic Acid ,Saccharomyces cerevisiae ,Computational biology ,Protein Serine-Threonine Kinases ,Biology ,Transfection ,Models, Biological ,Article ,Stress, Physiological ,Ergosterol ,Gene expression ,Genetics ,Gene Regulatory Networks ,Gene ,Regulation of gene expression ,Gene Expression Profiling ,Gene expression profiling ,Gene Expression Regulation ,alpha-Synuclein ,Genetic library ,Signal transduction ,Algorithms ,Heat-Shock Response ,Nitroso Compounds ,Signal Transduction ,Genetic screen - 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, yet the functional roles of the genes identified by these assays often remain enigmatic. By comparing the results of these two assays across various cellular responses, we found that they are consistently distinct. Moreover, genetic screens tend to identify response regulators, while 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 harnessed this approach to reveal cellular pathways related to alpha-synuclein, a small lipid-binding protein implicated in several neurodegenerative disorders including Parkinson disease. For this we screened an established yeast model for alpha-synuclein toxicity to identify genes that when overexpressed alter cellular survival. Application of our algorithm to these data and data from mRNA profiling provided functional explanations for many of these genes and revealed novel relations between alpha-synuclein toxicity and basic cellular pathways.
- Published
- 2009