Transmissible spongiform encephalopathies (TSEs or prion diseases) are a group of rare neurodegenerative diseases which include Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE) and chronic wasting disease (CWD) in mule deer and elk. TSE infectivity can cross species barriers. The fact that BSE has infected humans in Great Britain and concerns that CWD may act similarly in the US underscores the importance of understanding TSE pathogenesis and developing effective therapeutics. The infectious agent of TSE diseases is called a prion and is largely composed of an abnormally refolded, protease resistant form (PrP-res or PrPSc) of the normal, protease-sensitive prion protein, PrP-sen. Susceptibility to infection can be influenced by amino acid homology between PrP-sen and PrP-res while differences in structure between PrP-res molecules are believed to encode strain phenotypes. My studies address many different aspects of prion diseases at both the molecular and pathogenic level. In particular, my laboratory focuses on: 1) identifying the earliest events which occur during prion infection, 2) precisely defining the different cellular compartments where PrP-res formation occurs, 3) determining the molecular basis of prion strains and, 4) development of effective prion therapeutics. In most forms of prion disease, infectivity is present primarily in the central nervous system or immune system organs such as spleen and lymph node. However, studies in mice and non-human primates have shown that prions can also be present as amyloid deposits in heart tissue. Deposition of infectious prions as amyloid in human heart tissue would be a significant public health concern. In 2013, we completed and published studies to determine whether or not prion infectivity can be found in human heart tissue. We inoculated archival formaldehyde fixed brain and heart tissue from two sCJD patients, as well as prion protein positive fixed heart tissue from two amyloid heart disease patients, into a mouse model of human prion disease. Our results showed that: 1) prion infectivity is not likely present in cardiac tissue from sCJD patients, 2) prion infectivity is not associated with prion protein positive cardiac tissue from amyloid heart disease patients and, 3) prion infectivity can survive in archival brain histology specimens for decades. This work was published in 2013 in the Journal of Virology. One of the earliest events occurring in cells following exposure to an exogenous source of prions is the cellular uptake of PrP-res. It is unclear how the biochemical properties of PrP-res influence its uptake, although size is thought to be important. In 2013, we completed and published experiments characterizing the interaction of PrP-res with the cell during the initial stages of mouse prion infection. We show that, for two different prion strains, the vast majority of PrP-res taken up by the cell is limited to a specific aggregated fraction. However, the rate at which the cell breaks up the PrP-res aggregates is dependent upon the prion strain, with the strain that is unable to infect cells being broken up faster. This work is in press at the Journal of Virology. In 2013, we initiated in vivo work to look at early events during prion infection following intracranial inoculation. These studies will examine the early formation of PrP-res as well as changes in the expression of the host PrP-sen molecule during the acute stage of prion infection. Our work will provide critical information about the events that occur during the first few hours following exposure to prions, including when formation of new PrP-res occurs and how PrP-sen is affected. In 2013, we also initiated in vitro work to study how different human prion strains interact with human cell lines and began developing in vitro systems to study acute formation of human PrP-res. These studies will help us to understand how human prions interact with different cell types to trigger infection. Finally, in 2013 we initiated a collaboration with Dr. Mark Head and Dr. James Ironside at the CJD Surveillance unit in Edinburgh, Scotland. This collaboration involves using proteomics to study different human prion strains. These studies will provide insight into the pathogenesis and classification of different human prion diseases.
| Priola, Suzette A (2018) Cell biology of prion infection. Handb Clin Neurol 153:45-68 |
| Fehlinger, Andrea; Wolf, Hanna; Hossinger, André et al. (2017) Prion strains depend on different endocytic routes for productive infection. Sci Rep 7:6923 |
| Faris, Robert; Moore, Roger A; Ward, Anne et al. (2017) Cellular prion protein is present in mitochondria of healthy mice. Sci Rep 7:41556 |
| Marshall, Karen E; Hughson, Andrew; Vascellari, Sarah et al. (2017) PrP Knockout Cells Expressing Transmembrane PrP Resist Prion Infection. J Virol 91: |
| Priola, Suzette A (2017) Cell Biology Approaches to Studying Prion Diseases. Methods Mol Biol 1658:83-94 |
| Faris, Robert; Moore, Roger A; Ward, Anne et al. (2017) Mitochondrial Respiration Is Impaired during Late-Stage Hamster Prion Infection. J Virol 91: |
| Moore, Roger A; Head, Mark W; Ironside, James W et al. (2016) Correction: The Distribution of Prion Protein Allotypes Differs Between Sporadic and Iatrogenic Creutzfeldt-Jakob Disease Patients. PLoS Pathog 12:e1005496 |
| Skinner, Pamela J; Kim, Hyeon O; Bryant, Damani et al. (2015) Treatment of Prion Disease with Heterologous Prion Proteins. PLoS One 10:e0131993 |
| Priola, Suzette A; Ward, Anne E; McCall, Sherman A et al. (2013) Lack of prion infectivity in fixed heart tissue from patients with Creutzfeldt-Jakob disease or amyloid heart disease. J Virol 87:9501-10 |
| Chianini, Francesca; Fernández-Borges, Natalia; Vidal, Enric et al. (2012) Rabbits are not resistant to prion infection. Proc Natl Acad Sci U S A 109:5080-5 |
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