title: A systems approach to prion disease.
abstract: Prions cause transmissible neurodegenerative diseases and replicate by conformational conversion of normal benign forms of prion protein (PrP(C)) to disease-causing PrP(Sc) 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 PrP(Sc) 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.
authors.affiliation: Institute for Systems Biology, Seattle, WA 98103, USA.
authors.forename: Daehee
authors.initials: D
authors.lastname: Hwang
authors.forename: Inyoul Y
authors.initials: IY
authors.lastname: Lee
authors.forename: Hyuntae
authors.initials: H
authors.lastname: Yoo
authors.forename: Nils
authors.initials: N
authors.lastname: Gehlenborg
authors.forename: Ji-Hoon
authors.initials: JH
authors.lastname: Cho
authors.forename: Brianne
authors.initials: B
authors.lastname: Petritis
authors.forename: David
authors.initials: D
authors.lastname: Baxter
authors.forename: Rose
authors.initials: R
authors.lastname: Pitstick
authors.forename: Rebecca
authors.initials: R
authors.lastname: Young
authors.forename: Doug
authors.initials: D
authors.lastname: Spicer
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Price
authors.forename: John G
authors.initials: JG
authors.lastname: Hohmann
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Dearmond
authors.forename: George A
authors.initials: GA
authors.lastname: Carlson
authors.forename: Leroy E
authors.initials: LE
authors.lastname: Hood
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D018620:PrPSc Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000235:genetics*; D049490:Systems Biology / Q000379:methods*; D013997:Time Factors
chemical_list: D018620:PrPSc Proteins