Mechanisms of Prion Disease: Initial Misfolding of the Prion Protein and Metabolomic Changes in the Brain

• Author / Creator

  Fu, Zelin

• Prion diseases are neurodegenerative diseases that are caused by the misfolding and aggregation of cellular prion protein (PrPC) into the pathogenic form termed PrPSc. To contribute to a better understanding of the mechanism of prion disease, in this thesis I present my work on the structural characterization of a mutant of PrPC (HRdup), which led to genetic prion disease and the investigation of the brain metabolomic changes during prion disease progression. In Chapter 2, the structural stability of HRdup was examined as well as the structure of its canonical antiparallel beta-sheet. Detailed structural study of HRdup such as its backbone rigidity, is covered in Chapter 3. Combining the results from these two chapters, we learned the extra residues introduced by an insert to the central hydrophobic region of HRdup do not disrupt its canonical PrPC structure or have major effect on its structural stability, but a few of these residues in the insert displayed high beta-propensity which is indicative of an additional beta-turn in this otherwise disordered region. In Chapter 4, employing a novel metabolite extraction method, the brain metabolome of the mice inoculated with mice prion was analyzed along the progression of the disease. The brain metabolome profile consisted of 50 metabolites displayed continuous changes and the key metabolites were identified. These results contribute to a better understanding of the toxicity mechanism of prion disease, suggesting that tracking of neurochemical profiles could be effective in monitoring the progression of prion diseases as well as other neurodegenerative diseases. Chapter 5 summarized both research projects and expressed some of my thoughts about the future of both studies.

• Subjects / Keywords

  • NMR
  • Prion disease

• Graduation date

  Fall 2020

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-pmjr-q275

• License

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