Abstract
Prion diseases are a group of transmissible neurodegenerative diseases that affect a variety of animal species, including humans. The infectious agent is comprised of PrPSc, an abnormal isoform of the host-encoded prion protein, PrPC, and lacks a nucleic acid genome. Historically, prion strains have been defined by differences in the distribution and severity of spongiform degeneration and PrPSc deposition within the central nervous system (CNS) following experimental passage. However, while there is evidence to suggest that prion strain diversity is encoded by the conformation of PrPSc, the mechanisms responsible for strain-specific differences in neuropathology are not known. Potential mechanisms include strain-specific differences in 1) neuroanatomical transport, 2) neuronal susceptibility to infection, and 3) the efficiency of intracellular PrPSc accumulation.|To address the first possibility, the temporal and spatial spread of PrPSc in the CNS was assessed by immunohistochemistry following inoculation of hamsters in the sciatic nerve with either the hyper (HY) or drowsy (DY) strain of the transmissible mink encephalopathy (TME) agent. Both strains of the agent were transported via the same four descending motor tracts, suggesting that strain-specific differences in axonal transport do not exclusively determine prion strain targeting.|Additionally, the distinct neuropathological characteristics observed between strains are unlikely to be due to strain-specific neuronal susceptibility. Comparison of PrPSc deposition patterns by following different routes of infection indicated that all brain areas were susceptible to prion infection by both TME strains. However, differences were detected in the PrPSc deposition of strains in the dorsal root ganglia, indicating a strain-specific susceptibility of neurons in the peripheral nervous system.|To better understand the mechanisms by which PrPSc conformation affects prion strain properties, comparisons were made between the biochemical properties of eight hamster-adapted prion strains and their neuropathological characteristics. PrPSc from short incubation period strains was more efficiently replicated, had a more stable conformation, and was observed to be more resistant to clearance from the soma of neurons when compared to prion strains with a relatively long incubation period. These results suggest that the balance between PrPSc replication and clearance in neurons influences the progression of prion disease. Furthermore, the stability of a given prion strain conformation may affect its ability to replicate and its sensitivity to neuronal clearance.|The objectives for this dissertation were to understand the mechanisms responsible for prion strain targeting. This was accomplished by studying a number of potential mechanisms that may account for the strain specificity of prion-induced neuropathology.