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. An additional feature of prion infection of the central nervous system is extensive activation of microglia and astrocytes (gliosis) that accompanies neuronal loss in the brain as disease progresses. Dr. Carroll’s past research established that activated microglia are critical to host defense during prion infection, but the influence that astrocyte activation has on prion-induced neurodegeneration and disease progression are unknown. In our previous bulk RNAseq studies on microglia ablated brains during prion disease, we discovered a strong correlation between disease progression and increased astrocyte activation. Subsequently, Dr. Carroll has performed RNA sequencing of individual nuclei isolated from the thalamus of mice inoculated with RML prions. He compared preclinical or early clinical mouse samples to similarly analyzed uninfected mice using bioinformatic techniques. He has categorized 43 distinct cell clusters consisting of 10 different cell types. Bioinformatic analysis identified numerous pathways that are dysregulated in multiple cell types as prion disease progresses. Prominent in astrocytes was the increase in Jak-Stat pathway activation. Studies are ongoing to assess the specific role of the Jak-Stat pathway in prion-specific astrocyte activation and disease. Dr. Carroll also began a collaboration spanning the laboratories of Dr. Cathryn Haigh (Chief, Prion Cell Biology Unit, NIAID) and Dr. Bernardino Ghetti (Indiana University School of Medicine) to determine the genotype of sporadic Creutzfeldt-Jakob Disease patients at two distinct loci (ApoE and Tmem106b). Specific ApoE genotypes are associated with a greater risk for developing Alzheimer's disease, and Tmem106b amyloid filaments are associated with various neurodegenerative disorders. There is the possibility that polymorphisms at these loci might be influencing sporadic Creutzfeldt-Jakob Disease neuropathology. These genotypic differences in the patients will be correlated with several factors including sex, age at death, and primary neuropathological diagnosis. In addition, the lab has completed studies assessing cellular PrP (PrP-C) expression in retina of normal uninfected mice and compared these mice to uninfected PrP knockout (KO) mice in functional studies using electroretinogram (ERG) methodology. PrP-C was detected near the junctions between photoreceptors and bipolar cells by localization near synaptic proteins, EAAT5, CtBP2 and PSD-95. PrP-C appeared to be most dense on bipolar cell dendrites, which made synapses with cone photoreceptors. In two co-isogenic mouse strains of PrP-KO mice, significant alterations of the scotopic and/or photopic ERG responses of photoreceptors and bipolar cells were noted. Cone-dominant pathways showed the most significant ERG changes. Retinal thickness, quantitated by high-resolution optical coherence tomography, and ribbon synapse morphology were not altered upon deletion of PrP-C, suggesting that the ERG changes were driven by functional rather than structural alterations.