TY - JOUR
T1 - A comprehensive phylogeny of mammalian PRNP gene reveals no influence of prion misfolding propensity on the evolution of this gene
AU - Sampedro-Torres-Quevedo, Cristina
AU - Eraña, Hasier
AU - Charco, Jorge M.
AU - Díaz-Domínguez, Carlos M.
AU - San-Juan-Ansoleaga, Maitena
AU - Fernández-Muñoz, Eva
AU - Gonçalves-Anjo, Nuno
AU - Galarza-Ahumada, Josu
AU - Cortazar, Ana R.
AU - Nespolo, Roberto F.
AU - Quintero-Galvis, Julian F.
AU - Manero-Azua, Africa
AU - Polanco-Alonso, Diego
AU - Gaite-Reguero, Adrián
AU - Olalde, Íñigo
AU - Marigorta, Urko M.
AU - de Nanclares, Guiomar Perez
AU - Aransay, Ana M.
AU - Castilla, Joaquín
N1 - Publisher Copyright:
© 2025 Sampedro-Torres-Quevedo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2025/6
Y1 - 2025/6
N2 - Prion diseases are invariably fatal neurodegenerative diseases that affect some mammalian species, including humans. These diseases are caused by the misfolding of the cellular prion protein (PrPC) into a pathologic isoform (PrPSc). The prion protein is highly conserved across mammals. However, some species present lower susceptibility to prion diseases than others. This behavior is likely explained by the resistance of these animal species’ prion proteins to acquire a pathological conformation. Therefore, the tertiary structure and interspecific variations encoded in the primary structure determine a PrP proneness to misfolding. For this reason, we studied the PRNP gene from a phylogenetic perspective, potentially unveiling evolutionary events related to prion diseases. We generated a database of mammalian PRNP sequences and constructed phylogenetic trees based on nucleotide sequence variations. We aligned 1146 PRNP gene sequences from 900 different mammalian species and built a PRNP gene-based phylogenetic tree. Classical phylogenetic orders tend to maintain their clustering in the PRNP gene tree. 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 in vitro misfolding study. Protein Misfolding Shaking Amplification (PMSA) 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 and included analysis of different variants with a focus on the human rs1799990 locus (c.385A > G, p.Met129Val). This variant, widely linked to prion disease susceptibility in humans, is explored in the context of its evolutionary origins. All in all, our PRNP gene-based tree, despite showing some topological differences with the reference species tree that could be in some cases related to prion disease susceptibility, is not significantly distinct. Indicating that the proneness of a PrP variant to misfold spontaneously has not shaped the evolution of this gene.
AB - Prion diseases are invariably fatal neurodegenerative diseases that affect some mammalian species, including humans. These diseases are caused by the misfolding of the cellular prion protein (PrPC) into a pathologic isoform (PrPSc). The prion protein is highly conserved across mammals. However, some species present lower susceptibility to prion diseases than others. This behavior is likely explained by the resistance of these animal species’ prion proteins to acquire a pathological conformation. Therefore, the tertiary structure and interspecific variations encoded in the primary structure determine a PrP proneness to misfolding. For this reason, we studied the PRNP gene from a phylogenetic perspective, potentially unveiling evolutionary events related to prion diseases. We generated a database of mammalian PRNP sequences and constructed phylogenetic trees based on nucleotide sequence variations. We aligned 1146 PRNP gene sequences from 900 different mammalian species and built a PRNP gene-based phylogenetic tree. Classical phylogenetic orders tend to maintain their clustering in the PRNP gene tree. 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 in vitro misfolding study. Protein Misfolding Shaking Amplification (PMSA) 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 and included analysis of different variants with a focus on the human rs1799990 locus (c.385A > G, p.Met129Val). This variant, widely linked to prion disease susceptibility in humans, is explored in the context of its evolutionary origins. All in all, our PRNP gene-based tree, despite showing some topological differences with the reference species tree that could be in some cases related to prion disease susceptibility, is not significantly distinct. Indicating that the proneness of a PrP variant to misfold spontaneously has not shaped the evolution of this gene.
UR - https://www.scopus.com/pages/publications/105009966877
U2 - 10.1371/journal.ppat.1013257
DO - 10.1371/journal.ppat.1013257
M3 - Article
C2 - 40561181
AN - SCOPUS:105009966877
SN - 1553-7366
VL - 21
JO - PLOS Pathogens
JF - PLOS Pathogens
IS - 6
M1 - e1013257
ER -
