Transmissible Mink Encephaiopatby Strain-Specific Formation of the Abnormal Prion Protein
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Authors
Mulcahy, Ellyn Rosemarie
Issue Date
2002
Volume
Issue
Type
Dissertation
Language
en_US
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Abstract
Strain diversity among the prion diseases is proposed to be encoded by the conformation of the infectious isoform of the prion protein. PrPb PrPSc is derived from the nonnai host-encoded prion protein, PrP and this process had been modeled in an in vitro assay called the PrP cell-tree conversion reaction. The mechanism of conversion of PrPc to PrPSc is hypothesized to be the fundamental step in prion pathogenesis. Understanding the mechanism of how PrPSc formation occurs is crucial to the development of anti-prion drugs. The experiments described in this dissertation utilize the PrP cell-conversion reaction to investigate the strain-specific kinetics of PrPSc formation and to examine therapeutic compounds with anti-prion activity tor the inhibition of PrPSc* formation. Transmissible mink encephalopathy (TME) strains hyper (HY) and drowsy (DY) differ in the rates of PrPSc accumulation in vivo and in the conformation of their PrPSc molecules. HY and DY PrP conversion was examined in order to determine if the strain-specific properties of these two strains are mediated by strain-specific rates of PrP conversion. It was determined that PrP conversion proceeds via three distinct phases including a polymerization phase, a depolymerization phase and a steady-state phase. Strain-specific differences were identified between HY and DY PrP conversion during the polymerization phase of PrP conversion whereby HY TME had both a faster rate of PrP conversion and an earlier onset of peak PrP conversion than compared to DY TME. These results suggest that strain-specific rates of PrPSc accumulation in vitro are a result of the differential abilities of HY and DY PrPSc to convert PrPSc to a PrPSc-like molecule. Investigation of anti-prion drugs demonstrated that congo red (CR) and pnythalocyanine tetrasulfonate (PcTs) had the ability to inhibit HY and DY PrP conversion in a concentration-dependent manner. In contrast, amphotericin B (AmB), a drug that demonstrates anti-prion activity against other prion strains, did not have any effect on HY or DY PrP conversion. Pretreatment of PrPSc and PrPSc with CR or Pc fs ior two hours prior to the reaction did not result in the inhibition of HY or DY PrP conversion. This suggests that the concentration of anti-prion drug that binds to PrPSc or PrPSc is not sufficient to inhibit PrP conversion. This study demonstrates that the PrP cell-free conversion reaction is a useful assay to investigate the strain-specific properties of PrPSc formation and to screen compounds for anti-prion activity. The results of this study indicate that strain-specific properties of TME strains are retained and propagated in vivio by strain-specific conformations of PrPSc.
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Publisher
Creighton University
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