Dominant Negative Inhibition in Prion Protein

Mistica, Arla
A prion is a non-conventional pathogen that consists solely of the infections isoform of prion protein (PrP-SC). Prions do not have any nucleotide genome but it causes lethal neurodegenerative diseases including Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE) in cattle, and chronic wasting disease (CWD) in cervids. Prion infections occasionally pose threat to human health, for example, BSE in Europe and CWD in North America, whose zoonotic potential is still not fully understood. Currently, there is no accepted treatment for prion diseases. It is understood that the aggregation of PrP-SC, β-sheet rich isoform of the normal cellular prion protein, PrP-C, plays an important role in causing neurodegenerative diseases. Prions replicate by the constituent PrP-SC converting the host-encoded PrP-C into PrP-SC. My project aims to obtain further understanding of PrP-C to PrP-SC conversion. There is phenomenon called "Dominant-negative inhibition," where a conversion-incompetent mutant PrP-C (mutPrP) inhibits conversion of coexistent, conversion-competent PrP-C, presumably by occupying PrP-SC molecules to prevent it from binding to PrP-C. We utilized this phenomenon to identify the region necessary for the PrP-SC/PrP-C binding by making mutPrPs. As a result, deletions in a certain region of PrP were found to eliminate dominant-negative inhibition effect of the mutPrP.
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