Biology of Prion Protein and the TSE Diseases

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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 FY19, we extended our studies of the role of microglia in host defense against prion disease in vivo by following the progression of retina photoreceptor damage following prion infection via the intracerebral route. In retina, prion infection causes destruction of photoreceptor cells accompanied by a massive infiltration of microglia into the photoreceptor cell region. A similar pattern of pathology is seen in human retinitis pigmentosa associated with various mutations in proteins related to ocular function, and similar results have been seen in mouse models with these same mutations. Therefore, microglia are suspected to be important mediators of the pathogenic process in retinitis pigmentosa and this may also be true for prion-induced retinal disease. In FY19, we used oral treatment with a potent inhibitor of CSF-1R, PLX5622, to eliminate 78 to 90% of microglia from mouse central nervous system and retina shortly after and during the course of prion infection. Then we followed retinal pathology at various times post infection in mice with normal or ablated microglia. The results showed that prion retinal disease did not require the presence of microglia as mediators of pathogenesis. In fact, the destruction of photoreceptor cells was slightly faster in the absence of microglia. Thus, prion infection appeared to directly damage photoreceptor cells by forming deposits of aggregated abnormal prion protein located on the inner segment of the photoreceptor layer. Future experiments will be aimed at identifying more precisely the cell types targeted and the cellular location of the abnormal prion protein using ultrastructural examination and immunogold detection methods.