Prion diseases are fatal neurodegenerative disorders whose progression and transmission, unlike diseases caused by conventional pathogens, do not require a nucleic acid component. The infectious agent is the prion, a host-encoded protein which can exist as two structurally distinct isoforms: a monomeric cellular isoform found in normal tissues and an extracellular ordered aggregate only found in diseased individuals. A long standing mystery has been to understand the structural characteristics that lead to the aggregation of prion and the structural mechanism by which this aggregated form can self-propagate and be transmitted between individuals, and in certain cases, amongst species.;The following dissertation describes two routes by which we have taken steps towards understanding the structure and misfolding of prion into its infectious isoform: (i) a top down approach using x-ray crystallographic studies of small peptides derived from regions of prion shown be important in determining disease susceptibility, progression and transmissibility leading to a model that embodies these characteristics, and (ii) isolation and biochemical characterization of a small molecular weight oligomer of prion which can be used for future structural determination of the aggregated form.;Using these approaches, our results show the likely quaternary structure/structures of prion protein within the pathogenic isoform. We offer the first structural explanations of how these interactions result in the increased susceptibility of humans homozygous for a single nucleotide polymorphism in codon 129 in the prion gene, the artificial "species barrier" between human, mouse, and hamster prion cross-seeding, and a real life species barrier between prion disease in elk and humans.
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