A systems approach to prion disease.
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.
Hwang
Daehee
D
Institute for Systems Biology, Seattle, WA 98103, USA.
Lee
Inyoul Y
IY
Yoo
Hyuntae
H
Gehlenborg
Nils
N
Cho
Ji-Hoon
JH
Petritis
Brianne
B
Baxter
David
D
Pitstick
Rose
R
Young
Rebecca
R
Spicer
Doug
D
Price
Nathan D
ND
Hohmann
John G
JG
Dearmond
Stephen J
SJ
Carlson
George A
GA
Hood
Leroy E
LE
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
D018620:PrPSc Proteins