Dataset from thesis entitled: Analysis of the relationship between the phylogeny and the spontaneous misfolding proneness of the prion protein across hundreds of species of the class Mammalia.

<p>This entry contains raw data from the PhD thesis entitled "Analysis of the relationship between the phylogeny and the spontaneous misfolding proneness of the prion protein across hundreds of species of the class Mammalia." presented by Cristina Sampedro Torres-Quevedo in july 2024 at the University of the Basque Country (UPV/EHU).&nbsp;</p> <p>Among these raw data we include the alignment of 876 recombinant prion protein sequences from mammalian species, the phylogenetic tree that resulted from this alignment and PrPDex files that summarize the information obtained for many of the proteins included in the thesis (also available at prpdex.com).&nbsp;</p> <p>Abstract from the thesis:&nbsp;</p> <p>Transmissible spongiform encephalopathies (TSEs) or prion diseases are a group of invariably fatal neurodegenerative diseases that affect a range of mammalian species, including humans. These diseases are caused by the misfolding of the cellular prion protein (PrP^C) into a toxic, aggregation-prone isoform (PrP^Sc, from scrapie, the first identified prion disease). Despite this misfolding being the primary pathogenic event, the molecular mechanisms underlying this process remain largely unknown.</p> <p>The prion protein is highly conserved across species. However, despite the similarity between the amino acid sequences of the prion protein (PrP) among mammals, some species present much lower susceptibility to prion diseases. The key to this behaviour likely lays on the enhanced resistance of these animal species&rsquo; prion proteins to acquire a <em>bona fide</em> prion conformation. It is, therefore, conceivable that the tertiary structure and interspecific variations, ultimately encoded in the primary structure, determine the proneness of a PrP to misfolding. For this reason, the differences in the PrP sequence between mammalian species were systematically analysed to study the <em>PRNP</em> gene from a phylogenetic perspective, potentially unveiling evolutionary events related to prion diseases.</p> <p>A comprehensive database of hundreds of mammalian PrP sequences, the largest collection gathered so far, was generated, and phylogenetic trees were constructed based on nucleotide sequence variations. To this aim, 876 prion protein genetic sequences (from codon 90 to codon 231 approximately) from over 600 different mammalian species were aligned and a <em>PRNP</em> gene-based phylogenetic tree was built.</p> <p>Classical phylogenetic orders, classified according to multigenic analyses, tend to maintain their clusterization when using the <em>PRNP</em> gene as a readout of phylogenetic similarity. Nonetheless, the few differences found may shed some light on potential evolutionary constraints posed by prion disorders. Moreover, this phylogenetic study was combined with an <em>in vitro</em> misfolding study. The recently developed Protein Misfolding Shaking Amplification (PMSA), which allows to generate <em>bona fide</em> prions spontaneously, was used to evaluate the tendency of many of these proteins to misfold. This comprehensive analysis spanned a wide range of mammalian prion protein sequences. <span>&nbsp;</span></p> <p>This study has allowed to assign a numerical misfolding proneness score to each protein variant studied, ranking them based on their capacity to misfold spontaneously. Furthermore, this study presents data, on top of the tendency to misfold, on predicted protein stability, <em>in vitro </em>propagation, and <em>in vivo</em> infectious capabilities, whenever known. It also includes phylogenetic information about the species and lists of species with identical sequences.</p> <p>Both the phylogeny and misfolding studies have given rise to a large volume of data that may allow to determine the effect of distinct amino acids at each polymorphic position of the PrP on misfolding. This extremely complex phenomenon, influenced by multiple residues and the overall amino acidic context, will be the basis for future studies. These studies may require more sophisticated computational analyses or machine learning approaches than the visual analysis performed for this work. Nevertheless, our approach of coupling the phylogenetic information of the <em>PRNP</em> gene tree with misfolding capacity assessment has allowed us to conclude, among others, that prion diseases have not posed a constraint on the evolution of the <em>PRNP</em> gene. There are no clusters of phylogenetically distant species grouped by distinct prion-disease-resistant mutations. Moreover, the misfolding propensity does not correlate with general sequence similarity to the gold standard, the so-called universal prion acceptor, bank vole prion protein, nor with the predicted stability of the globular form of each PrP. In addition, from a more practical perspective, the resources and the wealth of data generated offer abundant models for structural and pathobiological studies. Among these, we can highlight designing new substrates for ultrasensitive prion detection methods, developing animal models with enhanced susceptibility to speed up preclinical studies, or designing dominant negative proteins for therapeutic applications.</p>