Differential gene expression during prion infection

Prion diseases (also known as transmissible spongiform encephalopathies, TSEs) are rare, infectious neurodegenerative disorders that affect a variety of mammals. TSE infections are inevitably fatal, with no known treatment or cure. The pathologic mechanism of TSEs is poorly understood, however, disease is thought to be caused by a misfolded form of the prion protein, termed PrP TSE. Additional hallmarks of prion infections include chronic neuroinflammation, spongiform degeneration and neuronal loss.;Identification of genes expressed in response to prion infection may identify factors involved in agent replication, mechanisms of neuropathology, biomarkers for disease and therapeutic targets. While many groups have sought to identify transcriptional changes specific to prion disease, chronic neuroinflammation, characteristic of TSEs, have made non-glial gene expression changes difficult to identify. We have successfully used the neurotoxicant cuprizone to qualitatively mimic the cell population changes observed in prion disease, resulting in both spongiform change and neuroinflammation. The use of cuprizone-treated animals as an experimental control during comparative gene expression profiling allowed for the identification of transcriptional changes that increase during prion disease and remain unchanged during cuprizone-triggered neuropathology, acting as a novel model for the neuropathological events occurring in the brain during prion disease. This model system has allowed for the identification of 17 transcripts unaffected by cuprizone treatment but increasing in expression during prion infection. Eleven of these transcripts show additional promise as biomarkers of prion disease as they are up-regulated during preclinical infection.;The role of the immune system is poorly understood during prion disease. Gene expression analysis has allowed us to identify the differential regulation of transcripts known to be induced by the immunoregulatory cytokine interferon gamma (IFN-gamma) in response to TSE infection. We have investigated the role of IFN-gamma on prion disease progression and gene expression during infection. Our results indicate that IFN-gamma is not essential for prion infection or for the up-regulation of "IFN-gamma induced" transcription, but may play a role in signaling for PrPTSE clearance during disease.