Gene expression alterations in brains of mice infected with three strains of scrapie

Abstract

Background: Transmissible spongiform encephalopathies (TSEs) or prion diseases are fatal neurodegenerative disorders which occur in humans and various animal species. Examples include Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in deer and elk, and scrapie in sheep, and experimental mice. To gain insights into TSE pathogenesis, we made and used cDNA microarrays to identify disease-associated alterations in gene expression. Brain gene expression in scrapie-infected mice was compared to mock-infected mice at pre-symptomatic and symptomatic time points. Three strains of mouse scrapie that show striking differences in neuropathology were studied: ME7, 22L, and Chandler/RML.

Results: In symptomatic mice, over 400 significant gene expression alterations were identified. In contrast, only 22 genes showed significant alteration in the pre-symptomatic animals. We also identified genes that showed significant differences in alterations in gene expression between strains. Genes identified in this study encode proteins that are involved in many cellular processes including protein folding, endosome/lysosome function, immunity, synapse function, metal ion binding, calcium regulation and cytoskeletal function.

Conclusion: These studies shed light on the complex molecular events that occur during prion disease, and identify genes whose further study may yield new insights into strain specific neuropathogenesis and ante-mortem tests for TSEs.

Figure 1

Different scans of the same hybridized microarray show different results. The representative hybridization results shown are from an ME7 infected mouse compared to a mock infected mouse. A) and B) show two scatter plots from two different scans of the same hybridized microarray. In each scatter plot, spot values from the mock infected animal are plotted on the X-axis and spots from scrapie infected animal are plotted on the Y-axis. Note that the scatter plots are different, and that in A) the spots more closely align with on the slope of 1 compared to the spots in B). The data from the scan presented in A) but not B) was used in these analyses.

Figure 2

Distinct patterns of alterations in gene expression produced by mouse scrapie strains ME7, 22L, and RML-Chandler. In this Cluster and TreeView representation of genes that differed significantly between strains, sample information is listed across the top. Each scrapie-infected mouse was compared to each of two mock-infected mice resulting in four hybridizations per strain (1a–4b). Replicate results are indicated as 1b–4b. GenBank accession numbers and gene symbols are indicated. Note the distinct patterns of altered gene expression between the three strains.