Gene-targeted mouse models provide novel insights into strain diversity and interspecies transmission of chronic wasting disease

Prion diseases are fatal, transmissible neurodegenerative diseases that affect humans and other animals and are caused by the aberrant misfolding of the prion protein (PrP) to a disease-causing form. The term 'prion' was coined in 1982 by Stanley Prusiner to denote a small proteinaceous infectious particle which is now known to be the cause of scrapie in sheep, transmissible mink encephalopathy (TME), bovine spongiform encephalopathy (BSE) in cattle, and chronic wasting disease (CWD) in cervids such as deer and elk. Additionally, humans can develop prion diseases via multiple routes – spontaneously in the case of sporadic Creutzfeldt-Jakob disease (CJD), inherited in the cases of fatal familial insomnia (FFI) and Gerstmann-Straussler-Scheinker (GSS) syndrome, or acquired in the cases of variant CJD and Kuru. In addition to classical prion diseases, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Frontotemporal dementia have recently been classified as prion-like diseases due to similar protein misfolding mechanisms critical to these disease pathogeneses. Thus, the exploration of prion disease mechanisms has implications for a variety of neurodegenerative diseases. The main focus of this thesis will be the characterization of CWD strains and pathogenesis using mouse models of CWD. The disease was first described in Colorado in the 1960s in mule deer and rocky mountain elk and since then has expanded in has expanded in both geographical range and host species range including white-tailed deer, moose, red deer and reindeer. In North America, CWD has now been documented in 30 American states and three provinces in Canada. In addition to cases in North America, CWD has been identified in South Korea as a result of accidental transmission of subclinically infected cervids from Canada. In 2015, Norway reported a case of CWD in a herd of reindeer, and shortly after also reported cases of CWD in three free-ranging moose, marking the first cases of CWD in Europe. As a result, surrounding countries increased CWD surveillance, and Finland reported two cases of CWD in moose, and Sweden reported four cases of CWD in moose. At the time of writing, 20 reindeer, 11 moose, and two red deer in Norway, four moose in Sweden, and two moose in Finland have been diagnosed as CWD positive in Europe. The persistent spread of CWD raises both ecological and economical concerns thus the characterization of CWD pathogenesis is of utmost importance. Prions are unlike viral and bacterial pathogens in that their infectious component is entirely proteinaceous. The templated conversion of PrPC to PrPSc is driven by PrPSc imposing its infectious conformation onto PrPC. In other words, there are no primary structural differences between PrPC and PrPSc and thus higher order structural differences between PrPC and PrPSc must account for infectivity of PrPSc. This is confirmed by recently solved cryogenic-electron microscopy structures of PrPSc which show an insoluble, β-sheet rich protein structure, as opposed to the soluble, α-helical rich PrPC conformation. Though all heritable information is encoded in protein conformation, prions can exhibit strain characteristics similar to other pathogens. Strains are operationally defined by characteristics such as time to disease onset, clinical signs, and neuropathology. While these characteristics can be defined in the natural disease host, the use of the mouse bioassay has facilitated the ease of strain typing. Since the primary structure of mouse PrP is slightly different than cervid PrP, transmission of CWD to mice is generally inefficient. Our and other labs combat this by the design of transgenic mice expressing cervid-PrP. Specifically, the Telling lab designed prototype transgenic overexpressing cervid-PrP mice, expressing either glutamate (E) or glutamine (Q) at residue 226 of PrP. This is the only primary structural difference between CWD susceptible cervid species: North American elk express E226, while deer, moose, and reindeer express Q226. Our lab then designed gene-targeted mice which express endogenous levels of cervid-PrP, either E226 or Q226 expressing. These mice serve as a proxy to characterize CWD strain characteristics and lend insight into the pathogenesis of CWD. The work included in this thesis largely utilizes these mice to answer fundamental questions pertaining to CWD. These questions include: 1. What effect does the polymorphism at residue 226 of cervid PrP have on CWD pathogenesis? 2. How do the strain profiles of emergent cases of Nordic CWD compare to well-characterized cases of North American CWD? 3. Did CWD originate from a cross species transmission, and what is the potential for further cross species transmission of CWD?

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