title: Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity.
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.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Esti
authors.initials: E
authors.lastname: Yeger-Lotem
authors.forename: Laura
authors.initials: L
authors.lastname: Riva
authors.forename: Linhui Julie
authors.initials: LJ
authors.lastname: Su
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
authors.forename: Anil G
authors.initials: AG
authors.lastname: Cashikar
authors.forename: Oliver D
authors.initials: OD
authors.lastname: King
authors.forename: Pavan K
authors.initials: PK
authors.lastname: Auluck
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Geddie
authors.forename: Julie S
authors.initials: JS
authors.lastname: Valastyan
authors.forename: David R
authors.initials: DR
authors.lastname: Karger
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
authors.forename: Ernest
authors.initials: E
authors.lastname: Fraenkel
mesh_terms: D000465:Algorithms; D004875:Ergosterol / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000235:genetics / Q000502:physiology*; D018869:Heat-Shock Response / Q000235:genetics; D008798:Mevalonic Acid / Q000378:metabolism; D008954:Models, Biological; D009603:Nitroso Compounds / Q000633:toxicity; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology; D014162:Transfection; D051844:alpha-Synuclein / Q000235:genetics / Q000633:toxicity*
chemical_list: D009603:Nitroso Compounds; D029701:Saccharomyces cerevisiae Proteins; D051844:alpha-Synuclein; D017346:Protein Serine-Threonine Kinases; C500749:target of rapamycin protein, S cerevisiae; D008798:Mevalonic Acid; D004875:Ergosterol