Modulation of Prion Protein Aggregate Size Composition to Study Effects on Cellular Transport and Propagation
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2018-01-26
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Abstract
Prion diseases are a group of detrimental neurodegenerative diseases that arise when the cellular prion glycoprotein is misfolded into a beta-sheet rich amyloidogenic isoform known as “PrPSc”. The accumulation and aggregation of this PrPSc in neuronal cells of the central nervous system leads to severe neurodegeneration and is fatal. With any given type of prion disease there is a vast array of different PrPSc aggregate sizes present, and it was previously found that the size of a PrPSc aggregate can influence certain properties, such as cellular uptake and transport. We were able to elucidate and compare the aggregate size profiles of the ME7 and 22L mouse-adapted scrapie strains using a sedimentation centrifugation technique. To better understand the effects of altering the prion protein aggregate size profile, we successfully utilized the chemical compound known as O4 to stabilize larger prion aggregates and therefore shifted the equilibrium towards the larger sizes. We showed that O4 was able to increase the proteolytic resistance of prion aggregates after stabilization, and reduced PrPSc levels in neuroblastoma cell models persistently infected with prions. In addition, we attempted to study the transport of prions across cellular barriers, through transcytosis, and how this might be related to aggregate size. Overall our work has furthered the understanding of the role that the aggregate size profile plays in prion diseases, and has given important insights as to how prion infection may be reduced or prevented.
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Kay, P. (2018). Modulation of Prion Protein Aggregate Size to Study Effects on Cellular Transport and Propagation (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/5471