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.