The Prion Protein: Modulation of Potassium Channels and a Novel Mouse Model of a Disease-Causing Hydrophobic Domain Insertion Mutation

• Author / Creator

  Mercer, Robert Corrigan Curtis

• Prion diseases are invariably fatal neurodegenerative diseases of humans and other mammals. While they can manifest as sporadic, infectious or genetic etiologies, the central event in prion disease is the structural conversion of the prion protein (PrPC) to an alternative conformer PrPSc. PrP is a highly enigmatic molecule with a wide range of proposed functions and disease associated phenotypes. A molecular understanding of the physiological function of PrP and the pathological characteristics of PrPSc is essential to uncover the means by which these diseases may be combatted. Herein, I describe two sets of analysis: i) the consequences of the physiological interaction between PrP and a potassium channel modulating protein, dipeptidyl aminopeptidase-like protein 6 (DPP6) and ii) the characterization of a novel mouse model of a genetic form of prion disease, Gerstmann–Sträussler–Scheinker disease (GSS). i) PrP, in a DPP6 dependent manner, enhances the properties of Kv4.2 voltage gated potassium channels such that there is an increase in peak amplitude, a rightward shift of the voltage-dependent steady-state inactivation curve, a slower inactivation, and a faster recovery from steady-state inactivation. ii) A patient presenting with GSS was found to harbor a novel insertion mutation of the hydrophobic domain of PrP. We created transgenic mice expressing this allele and present a biochemical and histopathological workup of these animals. They recapitulate many of the features of GSS, in particular a defining low molecular weight proteinase K resistant fragment of the prion protein. Brain extracts of affected animals can be used to accelerate disease in mice expressing the same insertion allele but wild type mice are refractory to this treatment.

• Subjects / Keywords

  • Prions
  • Potassium Channel
  • Gerstmann-Sträussler-Schienker
  • Neurodegeneration

• Graduation date

  Spring 2016

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R35H7C253

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.