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ToxSci Advance Access published online on October 16, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl131
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received June 19, 2006
Accepted October 15, 2006

Neurotoxicology

Chemical Genomic Profiling for Identifying Intracellular Targets of Toxicants Producing Parkinson's Disease

J. Doostzadeh 1 *, R. Davis 2, G. Giaever 3, C. Nislow 3, and J. W. Langston 1

1 The Parkinson's Institute, 1170 Morse Ave. Sunnyvale, CA, 94087, USA
2 Stanford Genome Technology Center 855 California Ave, CA, 940304, USA
3 Stanford Genome Technology Center 855 California Ave, CA, 940304, USA; University of Toronto Donnelley Centre for Cellular and Biomolecular Research, 160 College St, Toronto ON, M5S 3E1, Canada

* To whom correspondence should be addressed.
J. Doostzadeh, E-mail: jdoostzadeh{at}thepi.org


  Abstract

The yeast deletion collection includes ~4,700 strains deleted for both copies of every non-essential gene. This collection is a powerful resource for identifying the cellular pathways that functionally interact with drugs. In the present study the complete pool of ~4,700 barcoded homozygous deletion strains of Saccharomyces cerevisiae were surveyed to identify genes/pathways interacting with 1-methyl-4-phenylpyridinium (MPP+) and N,N-dimethyl-4-4-bipiridinium (paraquat), neurotoxicants that can produce Parkinson's disease. Each yeast mutant is molecularly ‘barcoded’ the collections can be grown competitively and ranked for sensitivity by microarray hybridization. Analysis data from these screens allowed us to determine that the multivesicular body pathway is an important element of toxicity induced by both MPP+ and paraquat. When yeast genes that when deleted showed sensitivity to MPP+ and paraquat toxicity were analyzed for their homology to human genes 80% were found to have have highly conserved human homologs (with e<10-8). Future work will address if these human genes may also functionally interact with MPP+ and paraquat toxicity.

Keywords: Chemogenomics; Neurotoxicants; Parkinson's disease.
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