Article abstract


Nature Genetics 41, 316 - 323 (2009)
Published online: 22 February 2009 | doi:10.1038/ng.337

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

Esti Yeger-Lotem1,2,8, Laura Riva1,8, Linhui Julie Su2, Aaron D Gitler2,7, Anil G Cashikar2,7, Oliver D King2,7, Pavan K Auluck2,3, Melissa L Geddie2, Julie S Valastyan2,4, David R Karger5, Susan Lindquist2,6 & Ernest Fraenkel1,5


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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  1. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
  2. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
  3. Departments of Pathology and Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, and Harvard Medical School, Boston, Massachusetts 02115, USA.
  4. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
  5. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
  6. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
  7. 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.).
  8. These authors contributed equally to this work.

Correspondence to: Susan Lindquist2,6 e-mail: lindquist_admin@wi.mit.edu

Correspondence to: Ernest Fraenkel1,5 e-mail: fraenkel-admin@mit.edu



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