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 vitro, infection of mouse scrapie-positive cells with the Moloney murine leukemia retrovirus can enhance the spread and release of mouse scrapie infectivity. These data suggested that co-infection of a prion-infected individual with a retrovirus could lead to exacerbation of prion disease. In 2012, we studied how retroviral co-infection influenced the progression of prion disease. Our results show that the murine leukemia virus Friend (F-MuLV) enhanced the release and spread of scrapie infectivity in cell culture but did not affect the pathogenesis of prion disease in vivo. This work was published in 2012 in PLoS One. In 2012, we completed in vivo work for the initial studies analyzing acute prion infection following sciatic nerve inoculation in mice. Based on those results, we have expanded the study to look at early events during prion infection following intracranial inoculation. We are also continuing in vitro studies begun last year aimed at characterizing the interaction of PrP-res with the cell during the initial stages of both mouse and human prion infection. Finally, in 2012 we completed a long-term collaborative project with Dr. Michael Oldstone assaying for prion infectivity in formalin-fixed paraffin embedded human brain and heart tissue from CJD and non-CJD patients. We anticipate that these data will be submitted for publication before the end of 2012.

Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2012
Total Cost
$498,151
Indirect Cost
City
State
Country
Zip Code
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
Moore, Roger A; Head, Mark W; Ironside, James W et al. (2016) The Distribution of Prion Protein Allotypes Differs Between Sporadic and Iatrogenic Creutzfeldt-Jakob Disease Patients. PLoS Pathog 12:e1005416
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
Timmes, Andrew G; Moore, Roger A; Fischer, Elizabeth R et al. (2013) Recombinant prion protein refolded with lipid and RNA has the biochemical hallmarks of a prion but lacks in vivo infectivity. PLoS One 8:e71081
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
Leblanc, Pascal; Hasenkrug, Kim; Ward, Anne et al. (2012) Co-infection with the friend retrovirus and mouse scrapie does not alter prion disease pathogenesis in susceptible mice. PLoS One 7:e30872
Moore, Roger A; Timmes, Andrew G; Wilmarth, Phillip A et al. (2011) Identification and removal of proteins that co-purify with infectious prion protein improves the analysis of its secondary structure. Proteomics 11:3853-65
Moore, Roger A; Timmes, Andrew; Wilmarth, Phillip A et al. (2010) Comparative profiling of highly enriched 22L and Chandler mouse scrapie prion protein preparations. Proteomics 10:2858-69
Belay, Ermias D; Schonberger, Lawrence B; Brown, Paul et al. (2010) Disinfection and sterilization of prion-contaminated medical instruments. Infect Control Hosp Epidemiol 31:1304-6; author reply 1306-8

Showing the most recent 10 out of 11 publications