A systems approach to prion disease

Top Cited Papers
Open Access
Publisher Website
Google Scholar
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. ### Synopsis A systems approach to disease postulates that disease arises from the pathological perturbation (genetic and/or environmental) of one or more biological networks in the relevant organ and hence to understand a disease one must study the dynamical changes in relevant biological networks during disease progression. We applied the systems approach analyzing brain transcriptomes to the experimentally tractable neurodegenerative diseases caused by prion infection of mice. Prions are unique among transmissible, disease‐causing agents in that they replicate by conformational conversion of normal benign forms of prion protein (PrPC) to disease‐specific PrPSc isoforms. Neuropathological features common to all prion diseases in mammals, which include bovine spongiform encephalopathy (BSE) in cows, Creutzfeldt–Jakob disease (CJD) in humans, and scrapie in sheep, can be conveniently subdivided into four well‐defined pathological processes: prion replication and PrPSc accumulation ([Prusiner, 2003][1]), synaptic degeneration ([Ishikura et al , 2005][2]), microglia and astrocyte activation ([Rezaie and Lantos, 2001][3]; [Perry et al , 2002][4]), and neuronal cell death ([Liberski et al , 2004][5]). Data on pathological changes in prion disease have been derived in multiple laboratories that have viewed prion‐induced neurodegeneration from different perspectives and with different preconceptions. Our comprehensive and independent systems analysis of the brain transcriptomes in normal and prion‐infected mice provides gene expression correlates with pathological information and will aid in organizing the current abundance of data fragments into a coherent pathogenic model of prion disease. We tracked global gene expression in the brains of eight distinct mouse strain–prion strain combinations at 8–10 time points throughout the incubation periods (60–350 days) to capture the effects of prion strain, host genetics, and PrP concentration on disease incubation time ([Figure 1][6]). Approximately 7400 genes were differentially expressed genes (DEGs) in one or more of the combinations. Subtractive analyses using three inbred mouse strains and two prion strains reduced the data dimensionality from 7400 to a core of 333 DEGs that reflected effects of prion strain and Prnp genotype that appeared central to prion disease. Of these, 178 had not previously been reported to change in prion‐infected mice. Gene expression results were combined with temporal patterns of PrPSc accumulation, pathology, gene ontology, protein interactions, and cell‐specific gene expression data to generate hypothetical dynamic protein networks that could be associated with known pathological events in disease progression; 231 DEGs were mapped into these networks. [Figure 4][7] is a snapshot of one of these networks (PrPSc accumulation) in a single mouse strain–prion strain combination at 14 weeks after inoculation, before any clinical signs are apparent. This figure includes a histoblot to track regional deposition of proteinase K‐resistant PrPSc in the brain; histoblots were collected at each time point for each prion strain–mouse strain combination. The previously unidentified DEGs and those that could not be readily assigned to networks likely encode previously unidentified aspects of prion disease and subsets of these may reveal involvement of modules reflecting androgenic steroid, iron, or arachidonate/prostaglandin metabolism. All data and tools used in these studies are available online in a prion disease database () Grouping mice in the five core prion strain–mouse strain combinations according to differences in incubation time revealed 55 DEGs, the expression of which was significantly enriched only in groups with short incubation times (B6‐RML, B6.I‐301V, and FVB‐RML). Similarly, grouping according to prion strain (RML or 301V) identified 39 DEGs enriched in RML prion‐inoculated mice. Interestingly, the emphasis on pathways such as cholesterol metabolism or glycosaminoglycan biosynthesis as central to prion disease may reflect the widespread use of RML and related prion isolates in short incubation time mice and in cell culture. The five core mouse strain–prion strain combinations emphasize incubation time differences reflecting interactions of PrPSc with PrPC encoded by alternative alleles of Prnp . PrPC concentration can also affect incubation time, and differential gene expression was explored in FVB.129‐ Prnp tm1Zrch/wt (0/+) mice that express half the normal amount of PrP and have a very long RML incubation time and in FVB‐Tg(PrP‐A)4053 (Tg4053) mice that overexpress PrP and have a very short...