Biology of Prion Protein and the TSE Diseases

National Institute Of Allergy And Infectious Diseases

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Abstract

Prion diseases or transmissible spongiform encephalopathies are infectious neurodegenerative diseases of humans and animals. A major feature of prion diseases is the refolding and aggregation of a normal host protein, prion protein (PrP), into a disease-associated protease-resistant form (PrPres) which may contribute to brain damage. In FY20 and FY21 we extended our studies of the role of astroglia and microglia in host defense against prion disease in vivo using RNA-seq technology, network analysis, and hierarchical cluster analysis to compare gene expression in brains of prion-infected versus mock-inoculated mice, as well as PLX5622-treated prion-infected mice. Prion infection of retina was also studied in mice, and was found to be focused mostly on photoreceptor cells (rods and cones). Cones were infected and damaged about 2 weeks prior to rods, but subsequently all the cells of both subtypes were destroyed and removed from the retina. The sites of PrPSc deposition in retina are being studied and the mechanisms of damage are also under investigation. In humans, development of familial prion disease due expression of mutant forms of prion protein usually leads to appearance of amyloid prion protein plaques in brain tissue containing both mutant prion protein and human phosphorylated tau protein. In our model expressing PrP lacking the GPI anchor moiety, prion infection also results in formation of amyloid plaques containing PrP. In the past we have attempted to test whether expression of human tau protein was able to increase amyloid plaques in the system. Mice were bred to express the appropriate proteins and then infected with prions. Although plaques were observed, the presence of human tau did appear to increase or decrease the process of amyloid deposition. Therefore, tau protein may not be a cofactor required in this disease.