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

Nat Genet. 2009 Mar;41(3):316-23. doi: 10.1038/ng.337. Epub 2009 Feb 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Algorithms
  • Ergosterol / metabolism
  • Gene Expression Profiling / methods
  • Gene Expression Regulation
  • Gene Regulatory Networks / genetics
  • Gene Regulatory Networks / physiology*
  • Heat-Shock Response / genetics
  • Mevalonic Acid / metabolism
  • Models, Biological
  • Nitroso Compounds / toxicity
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / physiology
  • Signal Transduction / genetics
  • Stress, Physiological / genetics
  • Transcription, Genetic / physiology
  • Transfection
  • alpha-Synuclein / genetics
  • alpha-Synuclein / toxicity*

Substances

  • Nitroso Compounds
  • Saccharomyces cerevisiae Proteins
  • alpha-Synuclein
  • Protein-Serine-Threonine Kinases
  • target of rapamycin protein, S cerevisiae
  • Mevalonic Acid
  • Ergosterol