A systems approach to prion disease

Daehee Hwang, Inyoul Y Lee, Hyuntae Yoo, Nils Gehlenborg, Ji-Hoon Cho, Brianne Petritis, David Baxter, Rose Pitstick, Rebecca Young, Doug Spicer, Nathan D Price, John G Hohmann (+3 others)
2009 Molecular Systems Biology  
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
more » ... enetics, 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. a End point is equivalent to the incubation time in this study, which is defined as the interval between prion inoculation to end point. With the exception of 0/0 mice, all animals were at the terminal stages of disease when killed for brain harvest. For each combination, a set of mice was inoculated with brain homogenate from normal mice and brains were harvested at the same time points as prion-infected mice. b Brains from three mice were taken at each time point. In a few instances, the interval deviated from that shown. For example, the final interval for B6-RML was 1 week due to severity of illness in these mice. The actual intervals are indicated in figures that follow. c Additional three RML-inoculated and three normal brain homogenate-inoculated 0/0 mice were aged 357 days (51 weeks).
doi:10.1038/msb.2009.10 pmid:19308092 pmcid:PMC2671916 fatcat:u7t2unnckzhwvkeaau64eqpvlu