Dissertation
Identifying factors that enhance prion accumulation in cultured sheep microglial cells
Washington State University
Doctor of Philosophy (PhD), Washington State University
12/2008
DOI:
https://doi.org/10.7273/000005962
Abstract
Transmissible spongiform encephalopathies (TSE, prion diseases) are invariably fatal, neurodegenerative diseases. Unlike other neurodegenerative diseases, such as Alzheimer's disease, many TSE are transmissible. Based on the protein-only hypothesis, this transmissibility is thought to be conferred by the ability of the abnormal isoform (PrPSc) to catalyze the conversion of the normal cellular form of the host encoded prion protein (PrPC) to additional PrPSc molecules. The conformational difference between PrPC and PrPSc is the abundance of beta-sheets within the PrPSc molecules, which renders PrPSc detergent insoluble and partially resistant to protease digestion. The stability of PrPSc results in the aggregation of PrPSc in affected tissues and serves as the marker for prion diseases. TSE can be found in many species and include scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease in deer and elk, and Creutzfeldt-Jakob disease (CJD) and kuru in humans. The similarities between scrapie and CJD have long been recognized and the use of scrapie as an experimental model allows for the investigation of a natural prion disease in a natural host. This work utilized a sheep-model of prion diseases to investigate the role of possible co-factors involved in the accumulation of PrPSc. In the first study, it was determined that coinfection of microglial cell cultures with both PrPScP and a noncytopathic small ruminant lentivirus (SRLV) resulted in a relative increase in the amount of PrPSc accumulated within and released by the cultured microglial. Additional studies are required to determine the biological significance and mechanism of this pathogen synergism. The second study sought to describe the cellular response of sheep microglia to accumulation of PrPSc in an attempt to identify proteins that might directly interact with PrPPC or PrPSc. Forty-nine genes were determined to be differentially regulated in this second study. Several of these genes have previously been determined to be differentially expressed in mouse and human models of prion disease. Determining if any of these identified genes play a direct role in the pathogenesis of prion diseases, requires additional studies.
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Details
- Title
- Identifying factors that enhance prion accumulation in cultured sheep microglial cells
- Creators
- James Brantly Stanton
- Contributors
- Timothy Baszler (Chair)Donald P. Knowles (Committee Member)Douglas Ruben Call (Committee Member) - Washington State University, Paul G. Allen School for Global Animal HealthKelly A. Brayton (Committee Member) - Washington State University, Department of Veterinary Microbiology and Pathology
- Awarding Institution
- Washington State University
- Academic Unit
- College of Veterinary Medicine
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 85
- Identifiers
- 99901055131801842
- Language
- English
- Resource Type
- Dissertation