, Inyoul Y Lee1,a
, Hyuntae Yoo1,a
, Nils Gehlenborg1,3
, Ji-Hoon Cho2
, Brianne Petritis1
, David Baxter1
, Rose Pitstick4
, Rebecca Young4
, Doug Spicer4
, Nathan D Price7
, John G Hohmann5
, Stephen J DeArmond6
, George A Carlson4
& Leroy E Hood1
1.Institute for Systems Biology, Seattle, WA, USA
2.I-Bio Program & Department of Chemical Engineering, POSTECH, Pohang, Republic of Korea
3.Microarray Team, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, UK
4.McLaughlin Research Institute, Great Falls, MT, USA
5.Allen Brain Institute, Seattle, WA, USA
6.Department of Pathology, University of California, San Francisco, CA, USA
7.Department of Chemical and Biomolecular Engineering & Institute for Genomic Biology, University of Illinois, Urbana, IL, USA
Correspondence to: George A Carlson4 McLaughlin Research Institute, 1520 23rd Street South, Great Falls, MT 59405, USA. Tel.: +1 406 454 6044; Fax: +1 406 454 6019.
Correspondence to: Leroy E Hood1 Institute for Systems Biology, 1441 North 34th Street, Seattle, WA 98103, USA. Tel.: +1 206 732 1201; Fax: +1 206 732 1254.
Received 27 November 2008; Accepted 20 January 2009; Published online 24 March 2009
This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits distribution and reproduction in any medium, provided the original author and source are credited. This licence does not permit commercial exploitation or the creation of derivative works without specific permission.
aThese authors contributed equally to this work
Prions cause transmissible neurodegenerative diseases and replicate by conformational conversion of normal benign forms of prion protein (PrPC) to disease-causing PrPSc isoforms. A systems approach to disease postulates that disease arises from perturbation of biological networks in the relevant organ. We tracked global gene expression in the brains of eight distinct mouse strain–prion strain combinations throughout the progression of the disease to capture the effects of prion strain, host genetics, and PrP concentration on disease incubation time. Subtractive analyses exploiting various aspects of prion biology and infection identified a core of 333 differentially expressed genes (DEGs) that appeared central to prion disease. DEGs were mapped into functional pathways and networks reflecting defined neuropathological events and PrPSc replication and accumulation, enabling the identification of novel modules and modules that may be involved in genetic effects on incubation time and in prion strain specificity. Our systems analysis provides a comprehensive basis for developing models for prion replication and disease, and suggests some possible therapeutic approaches.