A systems approach to prion disease |
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Authors: | Nils Gehlenborg Ji‐Hoon Cho Brianne Petritis David Baxter Rose Pitstick Rebecca Young Doug Spicer Nathan D Price John G Hohmann Stephen J DeArmond George A Carlson Leroy E Hood |
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Institution: | 1. Institute for Systems Biology, Seattle, WA, USA;2. Microarray Team, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, UK;3. I‐Bio Program & Department of Chemical Engineering, POSTECH, Pohang, Republic of Korea;4. McLaughlin Research Institute, Great Falls, MT, USA;5. Department of Chemical and Biomolecular Engineering & Institute for Genomic Biology, University of Illinois, Urbana, IL, USA;6. Allen Brain Institute, Seattle, WA, USA;7. Department of Pathology, University of California, San Francisco, CA, USA |
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Abstract: | 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. |
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Keywords: | microarray network analysis neurodegenerative disease prion |
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