Understanding the Effect of Disease-Related Mutations on Human Prion Protein Structure: Insights From NMR Spectroscopy

Abstract

Prion diseases or transmissible spongiform encephalopathies constitute a group of fatal neurodegenerative diseases that can be of sporadic, genetic, or acquired origin. The central molecular event of prion diseases is the conformational conversion of the physiological cellular prion protein, PrP^C, into a disease-associated form known as prion or PrP^Sc. Spontaneous generation of prions in genetic prion diseases is caused by mutations in the human prion protein gene (PRNP). Understanding of the earliest conformational changes during misfolding of PrP^C in genetic forms of prion diseases may benefit from detailed structural characterization of various human (Hu) PrP variants. Nuclear magnetic resonance (NMR) spectroscopy offers unique opportunities to obtain detailed atomic-level structure information. In this chapter we present an overview of high-resolution NMR studies on several HuPrPs with disease-associated mutations at mildly acidic and physiological pH conditions that provided valuable insights into possible key structural determinants underlying the formation of prions.

Keywords: Mutants; NMR spectroscopy; Prion diseases; Prion protein; Protective polymorphism; Structure determination; pH.