Prions are the causative agents of a group of transmissible degenerative brain diseases that are fatal to humans
and animals. The properties of the infectious agent and its mechanism of replication are unique. Prions are
comprised of PrPSc, an abnormally folded, aggregated version of its host-encoded counterpart protein (PrPC);
PrPSc self-replicates in the absence of informational nucleic acids by imposing its infectious conformation on
PrPC. Our poor understanding of the structural properties of PrPSc represents an important knowledge gap in
prion biology. This information is critical to elucidate the detailed mechanism of prion replication, the molecular
basis of prion strain variation, and the factors controlling prion transmission between species. In this project, we
focus on ascertaining the structural properties of prions causing chronic wasting disease (CWD), an
uncontrollable, contagious epidemic of North American deer, elk, and other members of the cervid family, which
is also emergent in Asian and European countries. The significant zoonotic potential and emergence of novel
strains have established CWD as a significant public health concern. The specific objectives of our research are
therefore (i) To determine structural properties of North American elk and deer CWD prions; (ii) To determine
the effects of primary structural variation at prion protein residue 226 and route of transmission on CWD prion
strain properties; and (iii) To determine the structural basis of strain variation in emerging Scandinavian CWD
strains and an adapted derivative. Our proposed studies are truly interdisciplinary since they combine the
complementary resources of two laboratories with expertise in novel mouse models for studying CWD, cell
culture approaches, biochemical assays, and a host of state-of-the-art methods of structural biology. The later
include several complementary mass spectrometry-based structural methods and cryo-electron microscopy, an
emerging approach with high potential for providing long-sought insights into high-resolution structures of
different prion strains.