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PMID: 19234470 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Validation Study

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

Nature genetics ·Vol. 41 ·No. 3 ·2009-03-00 ·Pages 316-23

Yeger-Lotem E, Riva L, Su LJ, Gitler AD, Cashikar AG, King OD, Auluck PK, Geddie ML, Valastyan JS, Karger DR, Lindquist S, Fraenkel E

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.

MeSH Terms
Algorithms Ergosterol/metabolism Gene Expression Profiling/methods Gene Expression Regulation Gene Regulatory Networks/genetics,physiology Heat-Shock Response/genetics Mevalonic Acid/metabolism Models, Biological Nitroso Compounds/toxicity Protein Serine-Threonine Kinases/genetics,physiology Saccharomyces cerevisiae/genetics Saccharomyces cerevisiae Proteins/genetics,physiology Signal Transduction/genetics Stress, Physiological/genetics Transcription, Genetic/physiology Transfection alpha-Synuclein/genetics,toxicity
Chemicals
Nitroso Compounds Saccharomyces cerevisiae Proteins alpha-Synuclein Protein Serine-Threonine Kinases target of rapamycin protein, S cerevisiae Mevalonic Acid Ergosterol
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Yeger-Lotem Esti
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Riva Laura
Su Linhui Julie
Gitler Aaron D
Cashikar Anil G
King Oliver D
Auluck Pavan K
Geddie Melissa L
Valastyan Julie S
Karger David R
Lindquist Susan
Fraenkel Ernest
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.337
Published
2009-03-00
Epub
2009-00-22
Pages
316-23
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC2733244
Subset
IM
Grants
Howard Hughes Medical Institute · United States
NINDS NIH HHS · P50 NS038372 · United States
NINDS NIH HHS · P50 NS038372-100005 · United States
NINDS NIH HHS · NS38372 · United States
External Links
PubMed source DOI: 10.1038/ng.337 PMC Full Text View journal details
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