Insight From Animals Resistant to Prion Diseases: Deciphering the Genotype – Morphotype – Phenotype Code for the Prion Protein

Research output: Contribution to journalReview articlepeer-review

Abstract

Prion diseases are a group of neurodegenerative diseases endemic in humans and several ruminants caused by the misfolding of native prion protein (PrP) into pathological conformations. Experimental work and the mad-cow epidemic of the 1980s exposed a wide spectrum of animal susceptibility to prion diseases, including a few highly resistant animals: horses, rabbits, pigs, and dogs/canids. The variable susceptibility to disease offers a unique opportunity to uncover the mechanisms governing PrP misfolding, neurotoxicity, and transmission. Previous work indicates that PrP-intrinsic differences (sequence) are the main contributors to disease susceptibility. Several residues have been cited as critical for encoding PrP conformational stability in prion-resistant animals, including D/E159 in dog, S167 in horse, and S174 in rabbit and pig PrP (all according to human numbering). These amino acids alter PrP properties in a variety of assays, but we still do not clearly understand the structural correlates of PrP toxicity. Additional insight can be extracted from comparative structural studies, followed by molecular dynamics simulations of selected mutations, and testing in manipulable animal models. Our working hypothesis is that protective amino acids generate more compact and stable structures in a C-terminal subdomain of the PrP globular domain. We will explore this idea in this review and identify subdomains within the globular domain that may hold the key to unravel how conformational stability and disease susceptibility are encoded in PrP.

Original languageEnglish (US)
Article number254
JournalFrontiers in Cellular Neuroscience
Volume14
DOIs
StatePublished - Aug 18 2020

Bibliographical note

Funding Information:
We thank the RSCB Protein Data Bank, and ClustalW2 for free data and software, and the University of Minnesota Information Technology Support Services for institutional copy of and PyMOL. Funding. This work was supported by the Winston and Maxine Wallin Neuroscience Discovery Fund award CON000000083928 to PF-F and AC.

Keywords

  • amino acid substitution
  • animal models
  • disease susceptibility
  • prion disease
  • prion protein
  • protein structure
  • structure–function

PubMed: MeSH publication types

  • Journal Article
  • Review

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