Elucidating the mechanism of prion replication promiscuity

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The presence of misfolded, aggregated proteins in the brain is a hallmark of many human neurodegenerative diseases. Of particular interest are the prion diseases, which include Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE, or "mad cow disease") in cattle. In these diseases, misshapen proteins called prions accumulate in the brain, eventually resulting in the death of brain cells. Prions are notorious for being infectious proteins. Generally, prions from one species do not efficiently infect other species, a process referred to as the "species barrier". Sometimes, the species barrier is imperfect, as in the case of the transmission of BSE prions to humans during the mad cow disease epidemic in the United Kingdom. Some animal species, such as rabbits and dogs, are seemingly resistant to prion disease. At the other end of the spectrum, bank voles (Myodes glareolus) are susceptible to prions from many different species, suggesting that they do not impose a species barrier for prions. Thus, bank voles provide a unique opportunity to study the transfer of prions from one species to another. My previous work has demonstrated that bank voles produce a prion protein that is extremely susceptible to misfolding both spontaneously and upon exposure to prions from other species. The objectives of this Discovery Grant are to determine why the bank vole prion protein is "promiscuous" for replicating prions and why it is much more prone to misfolding than prion proteins from other species. To accomplish these goals, we will utilize a multi-faceted approach involving purified proteins, cultured cells, and genetically engineered mice in conjunction with powerful biochemical tools for studying protein misfolding. This research will provide insight into the molecular details of prion misfolding and interspecies prion transmission. More generally, this work has important implications for understanding why proteins misfold, preventing future outbreaks of prion disease, and for developing strategies to prevent or reverse protein aggregation in the brain.