Insight From Animals Resistant to Prion Diseases: Deciphering the Genotype – Morphotype – Phenotype Code for the Prion Protein
| Autor: | Pedro Fernandez-Funez, Alessandro Cembran, Ryan R. Myers |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
structure–function animal diseases prion disease Review Disease Biology lcsh:RC321-571 03 medical and health sciences Cellular and Molecular Neuroscience Disease susceptibility 0302 clinical medicine Protein structure Genotype medicine Prion protein protein structure lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry chemistry.chemical_classification Genetics Neurotoxicity disease susceptibility medicine.disease Phenotype animal models Amino acid nervous system diseases 030104 developmental biology chemistry prion protein 030217 neurology & neurosurgery Neuroscience amino acid substitution |
| Zdroj: | Frontiers in Cellular Neuroscience, Vol 14 (2020) Frontiers in Cellular Neuroscience |
| ISSN: | 1662-5102 |
| DOI: | 10.3389/fncel.2020.00254/full |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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